The Health
Cdnsequences
Of Smoking

NICOTINE ADDICTION

a report of the
Surgeon General

1988

US. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health &vke
Cmlen for Disease Control
Cenlw for Healfh Plomofkn and Educatkn
Offke on Smoldng and Health
Rockvllk, Maryland 20857

For sale by the Superintendent of Documents, U.S. Government Printing Office
            Washingtoa, D.C. 20402


The Honorable James Wright
Speaker of the House
of Representatives
Washington, D.C.  20515

Dear Hf. Speaker:

I am pleased to transmit to the Congress the 1987 Surgeon General's Report on
the health consequences of smoking, as mandated by Section B(a) of the Public
Health Cigarette Smoking Act of 1969.  The Act requires the Secretary of
Health and Human Services to transmit a" annual report to Congress on the
health consequences of smoking and such recommendations for legislation as the
Secretary may deem appropriate.

This report, entitled The Health Consequences of Smoking: Nicotine Addiction,
examines the scientific evidence that cigarettes and other forms of tobacco
are addicting.  The issue of tobacco addiction has been addressed in previous
Surgeon General's Reports and in the medical literature beginning in the early
1900s.  Because of the recent expansion of research in this area, a thorough
review of this topic is warranted.  Despite the significant health risks of
tobacco use outlined in previous reports, many smokers have great difficulty
in quitting.  This report concludes that such difficulty is in large part due
to the addicting properties of nicotine, which is present in all forms of
tobacco.

The report further concludes that the processes that determine tobacco
addiction are similar to those that determine addiction to other drugs such as
heroin and cocaine.  Through such understanding, health-care providers may be
better able to assist tobacco users in quitting.

Private health organizations, health-care providers, community groups. and
government agencies should initiate or strengthen programs to inform the
public of the addicting nature of tobacco use.  A warning label on the
addicting nature of tobacco use should be rotated with other health warnings
now required on cigarette and smokeless tobacco packages and advertisements.
Preventing the initiation of tobacco use must be a priority because of the
difficulty in overcoming "icocine addiction once it is firmly established.
Because most cases of nicotine addiction begin during childhood and
adolescence, school curricula on the prevention of drug use should also
include tobacco.

Cigarette smoking, the chief avoidable cause of premature death in this
country, is responsible for mare than 300,000 premature deaths each year. The
disease impact of smoking justifies placing the problem of tobacco use at the
top of the public health agenda.  The conclusions of this report provide
another compelling reason for strengthening our efforts to reduce tobacco use
in our society.

                         Sincerely,
          f$&--- `4.y
                         Otis R. Bane", Y.D.
                         %YPZt*ry

Enclosure


The Honorable George Bush
President of the Senate
Washington, D.C. 20515

Deer Hr. Presfdent:

I am pleased to transmit t" the Congress the 1987 Surgeon General's Report an
the health consequences of smoking, as mandated by Section g(a) of. the Public
Health Cigarette Smoking Act of 1969.  The Act requires the Secretary of
Health and Human Services to transmit an annual report t" Congress on the
health consequences of smoking end such recommendations for legislation as the
Secretary may deem appropriate.

This report, entitled The Health Consequences of Smoking: Nicotine Addiction,
examines the scientific evidence that cirarettes and other forma of tobacco
are addicting.  The issue of tobacco addrction has been addressed in previous
Surgeon General's Reports end in the medical literature beginning in the early
1900s.  Because of the recent expansion of research in this area, a thorough
revi.& of this topic is warranted.  Despite the significant health risks of
tobacco "se outlined in previous reports, many smokers have great difficulty
in quitting.  This report concludes that such difficulty is in large part due
t" the addicting properties of nicotine, which is present i" all forms of
tobacco.

The report further concludes that the processes that determine tobacco
addiction are similar to those that determine addiction to other drugs such as
heroin and cocaine.  Through such understanding, health-care providers may be
better able to assist tobacco users in quitting,

Private health organizations, health-care providers, community groups. and
government agencies should initiate or strengthen programs to inform the
public of the addicting nature of tobacco use.  A vaming label on the
addicting "ature of tobacco use should be rotated vith other health warnings
now required on cigarette and swkelesa tobacco packages and advertisements.
Preventing the initiation of tobacco use must be a priority because of the
difficulty in overcoming "icotfne addiction once it is firmly established.
Because m"st cases of nicotine addiction begin during childhood and
adolescence, school curricula on the prevention of drug use should also
include tobacco.

Cigarette smoking, the chief avoidable cause of premature death in this
country, is responsible for more than 300,000 premature deaths each year. The
disease impact of smoking justifies placing the problem of tobacco use at the
top of the public health agenda.  The conclusions of this report provide
another compelling Peas"" for strengthening "UT efforts to reduce tobacco use
in our society.

Sincerely,

C&=5---&
Otis R. Boven, H.D.
Secretary


FOREWORD

This 20th Report of the Surgeon General on the health conse-
quences of tobacco use provides an additional important piece of
evidence concerning the serious health risks associated with using
tobacco.

The subject of this Report, nicotine addiction, was first mentioned
in the 1964 Report of the Advisory Committee to the Surgeon
General, which referred to tobacco use as "habituating." In the
landmark 1979 Report of the Surgeon General, by which time
considerably more research had been conducted, smoking was called
"the prototypical substance-abuse dependency." Scientists in the
field of drug addiction now agree that nicotine, the principal
pharmacologic agent that is common to all forms of t.obacco, is a
powerfully addicting drug.

Recognizing tobacco use as an addiction is critical both for treating
the tobacco user and for understanding why people continue to use
tobacco despite the known health risks. Nicotine is a psychoactive
drug with actions that reinforce the use of tobacco. Effort,s to reduce
tobacco use in our society must address all the major influences that
encourage continued use, including social, psychological, and phar-
macologic factors.

After carefully examining the available evidence, this Report
concludes that:

o Cigarettes and other forms of t,obacco are addicting.
o Nicotine is the drug in tobacco that causes addiction.
o The pharmacologic and behavioral processes that determine
   tobacco addiction are similar to those that determine addiction
  to drugs such as heroin and cocaine.
We must recognize both the potential for behavioral and pharma-
cologic treatment of the addicted tobacco user and the problems of
withdrawal. Tobacco use is a disorder which can be remedied
through medical attention; therefore, it should be approached by
health care providers just as other substance-use disorders are
approached: with knowledge, understanding, and persistence. Each
health care provider should use every available c!inical opportunity
to encourage or assist smokers to quit and to help former smokers to
maintain abstinence.


To maintain momentum toward a smoke-free society, we also must
take steps to prevent young people from beginning to smoke. First,
we must insure that every child in every school in this country is
educated as to the health risks and the addictive nature of tobacco
use. Most jurisdictions require that school curricula include preven-
tion of drug use; therefore, education on the prevention of tobacco
use should be included in this effort. Second, warning labels
regarding the addictive nature of t,obacco use should be required for
all tobacco packages and advertisements. Young people in particular
may not be aware of the risk of tobacco addiction. Finally, parents
and other role models should discourage smoking and other forms of
tobacco use among young people. Parents who quit set an example
for their children.

Smoking continues to be the chief preventable cause of premature
death in this country. Nicotine has addictive properties which help
to sustain widespread tobacco use. It is gratifying to see the decline
in reported smoking prevalence and cigarette consumption in the
United States during the past 25 years. However, we cannot expect
to see a sustained decline in rates of smoking-related cancers,
cardiovascular disease, and pulmonary disease without sustained
public health efforts against tobacco use.

The Public Health Service is committed to preventing tobacco use
among youth and to promoting cessation among existing smokers.
We hope that this Report will assist the health care community,
voluntary health agencies, and our Nation's schools in working with
us to reduce tobacco use in our society.

Robert E. Windom, M.D.
Assistant Secretary for Health

ii


PREFACE

This Report of the Surgeon General is the U.S. Public Health
Service's 20th Report on the health consequences of tobacco use and
the 7th issued during my tenure as Surgeon General. Eighteen
Reports have been released previously as part of the health
consequences of smoking series; a report on the health consequences
of using smokeless tobacco was released in 1986.

Previous Rep0rt.s have reviewed the medical and scientific evi-
dence establishing the health effects of cigarette smoking and other
forms of tobacco use. Tens of thousands of studies have documented
that smoking causes lung cancer, other cancers, chronic obstructive
lung disease, heart disease, complications of pregnancy, and several
other adverse health effects.

Epidemiologic studies have shown that cigarette smoking is
responsible for more than 300,000 deaths each year in the United
States. As I stated in the Preface to the 1982 Surgeon General's
Report, smoking is the chief avoidable cause of death in our society.

From 1964 through 1979, each Surgeon General's Report ad-
dressed the major health effects of smoking. The 1979 Report
provided the most comprehensive review of these effects. Following
the 1979 Report, each subsequent Report has focused on specific
populations (women in 1980, workers in 19851, specific diseases
(cancer in 1982, cardiovascular disease in 1983, chronic obstructive
lung disease in 19841, and specific topics (low-tar. low-nicotine
cigarettes in 1981, involuntary smoking in 1986).

This Report explores in great detail another specific topic: nicotine
addiction. Careful examination of the data makes it clear that
cigarettes and other forms of tobacco are addicting. An extensive
body of research has shown that nicotine is the drug in tobacco that
causes addiction. Moreover, the processes that determine tobacco
addiction are similar to those that determine addiction to drugs such
as heroin and cocaine.

Actions of Nicotine

All tobacco products contain substantial amounts of nicotine.
Nicotine is absorbed readily from tobacco smoke in the lungs and
from smokeless tobacco in the mouth or nose. Levels of nicotine in

. . .
111


the blood are similar in magnitude in people using different forms of
tobacco. Once in the blood stream, nicotine is rapidly distributed
throughout the body.

Nicotine is a powerful pharmacologic agent that acts in a variety
of ways at different sites in the body. After reaching the blood
stream, nicotine ent,ers the brain, interacts with specific receptors in
brain tissue. and initiates metabolic and electrical activity in the
brain. In addition, nicotine causes skeletal muscle relaxation and
has cardiovascular and endocrine (i.e., hormonal) effects.

Human and animal studies have shown that nicotine is the agent
in tobacco that leads to addiction. The diversity and strength of its
actions on the body are consistent with its role in causing addiction.

Tobacco Use as an Addiction

Standard definitions of drug addiction have been adopted by
various organizations including the World Health Organization and
the American Psychiatric Association. Although these definitions
are not identical, they have in common several criteria for establish-
ing a drug as addicting.

The central element among all forms of drug addiction is that the
user's behavior is largely controlled by a psychoactive substance (i.e.,
a substance that produces transient alterations in mood that are
primarily mediated by effects in the brain). There is often compul-
sive use of the drug despite damage to the individual or to society,
and drug-seeking behavior can take precedence over other important
priorities. The drug is "reinforcing"-that is, the pharmacologic
activity of the drug is sufficiently rewarding to maintain self-
administration. "Tolerance" is another aspect of drug addiction
whereby a given dose of a drug produces less effect or increasing
doses are required to achieve a specified intensity of response.
Physical dependence on the drug can also occur, and is characterized
by a withdrawal syndrome that usually accompanies drug absti-
nence. After cessation of drug use, there is a strong tendency to
relapse.

This Report demonstrates in detail that tobacco use and nicotine
in particular meet all these criteria. The evidence for these findings
is derived from animal studies as well as human observations.
Leading national and international organizations, including the
World Health Organization and the American Psychiatric Associa-
tion, have recognized chronic tobacco use as a drug addiction.

Some people may have difficulty in accepting the notion that
tobacco is addicting because it is a legal product. The word
"addiction" is strongly associated with illegal drugs such as cocaine
and heroin. However, as this Report shows, the processes that


determine tobacco addiction are similar to those that determine
addiction to other drugs, including illegal drugs.

In addition, some smokers may not believe that tobacco is
addicting because of a reluctance to admit that one's behavior is
largely controlled by a drug. On the other hand, most smokers admit
that they would like to quit but have been unable to do so. Smokers
who have repeatedly failed in their attempts to quit probably realize
that smoking is more than just a simple habit.

Many smokers have quit on their own ("spontaneous remission")
and some smokers smoke only occasionally. However, spontaneous
remission and occasional use also occur with the illicit drugs of
addiction, and in no way disqualify a drug from being classified as
addicting. Most narcotics users, for example, never progress beyond
occasional use, and of those who do, approximately 30 percent
spontaneously remit. Moreover, it seems plausible that spontaneous
remitters are largely those who have either learned to deliver
effective treatments to themselves or for whom environmental
circumstances have fortuitously changed in such a way as to support
drug cessation and abstinence.

Treatment

Like other addictions, tobacco use can be effectively treated. A
wide variety of behavioral interventions have been used for many
years, including aversion procedures (e.g., satiation, rapid smoking),
relaxation training, coping skills training, stimulus control, and
nicotine fading. In recognition of the important role that nicotine
plays in maintaining tobacco use, nicotine replacement therapy is
now available. Nicotine polacrilex gum has been shown in controlled
trials to relieve withdrawal symptoms. In addition, some (but not all)
studies have shown that nicotine gum, as an adjunct to behavioral
interventions, increases smoking abstinence rates. In recent years,
multicomponent interventions have been applied successfully to the
treatment of tobacco addiction.

Public Health Strategies

The conclusion that cigarettes and other forms of tobacco are
addicting has important implications for health professionals, educa-
tors, and policy-makers. In treating the tobacco user, health profes-
sionals must address the tenacious hold that nicotine has on the
body. More effective interventions must be developed to counteract
both the psychological and pharmacologic addictions that accompa-
ny tobacco use. More research is needed to evaluate how best to treat
those with the strongest dependence on the drug. Treatment of
tobacco addiction should be more widely available and should be

V


considered at least as favorably by third-party payors as treatment of
alcoholism and illicit drug addiction.

The challenge to health professionals is complicated by the array
of new nicotine delivery systems that are being developed and
introduced in the marketplace. Some of these products are produced
by tobacco manufacturers; others may be marketed as devices to aid
in smoking cessation. These new products may be more toxic and
more addicting than the products currently on the market. New
nicotine delivery systems should be evaluated for their toxic and
addictive effects; products intended for use in smoking cessation also
should be evaluated for efficacy.

Public information campaigns should be developed to increase
community awareness of the addictive nature of tobacco use. A
health warning on addiction should be rotated with the other
warnings now required on cigarette and smokeless tobacco packages
and advertisements. Prevention of tobacco use should be included
along with prevention of illicit drug use in comprehensive school
health education curricula. Many children and adolescents who are
experimenting with cigarettes and other forms of tobacco state that
they do not intend to use tobacco in later years. They are unaware of,
or underestimate, the strength of tobacco addiction. Because this
addiction almost always begins during childhood or adolescence,
children need to be warned as early as possible, and repeatedly
warned through their teenage years, about the dangers of exposing
themselves to nicotine.

This Report shows conclusively that cigarettes and other forms of
tobacco are addicting in the same sense as are drugs such as heroin
and cocaine. Most adults view illegal drugs with scorn and express
disapproval (if not outrage) at their sale and use. This Nation has
mobilized enormous resources to wage a war on drugs - illicit drugs.
We should also give priority to the one addiction that is killing more
than 300,000 Americans each year.

We as citizens, in concert with our elected officials, civic leaders,
and public health officers, should establish appropriate public
policies for how tobacco products are sold and distributed in our
society. With the evidence that tobacco is addicting, is it appropriate
for tobacco products to be sold through vending machines, which are
easily accessible to children? Is it appropriate for free samples of
tobacco products to be sent through the mail or distributed on public
property, where verification of age is difficult if not impossible?
Should the sale of tobacco be treated less seriously than the sale of
alcoholic beverages, for which a specific license is required (and
revoked for repeated sales to minors)?

In the face of overwhelming evidence that tobacco is addicting,
policy-makers should address these questions without delay. To

vi


achieve our goal of a smoke-free society, we must give this problem
the serious attention it deserves.

C. Everett Koop, M.D., Sc.D.
Surgeon General

vii


ACKNOWLEDGMENTS

This Report was prepared by the Department of Health and
Human Services under the general editorship of the Office on
Smoking and Health, Ronald M. Davis, M.D., Director. The Manag-
ing Editors were Thomas E. Novotny, M.D., and William R. Lynn,
Office on Smoking and Health.

Scientific editors were Neal L. Benowitz, M.D., Professor of
Medicine, Chief, Division of Clinical Pharmacology and Experimen-
tal Therapeutics, San Francisco General Hospital, University of
California, San Francisco, California; Neil E. Grunberg, Ph.D.,
Department of Medical Psychology, Uniformed Services University
of the Health Sciences, Bethesda, Maryland; Jack E. Henningfield,
Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment
Laboratory, Addiction Research Center, National Institute on Drug
Abuse, Baltimore, Maryland; and Harry A. Lando, Ph.D., Professor,
Department of Psychology, Iowa State University, Ames, Iowa.

The following individuals prepared draft chapters or portions of
the Report.

David B. Abrams, Ph.D., Assistant Professor of Psychiatry and
Human Behavior, Brown University Program in Medicine, The
Miriam Hospital, Center for Health Promotion, Providence, Rhode
Island

Timothy B. Baker, Ph.D., Department of Psychology, University of
Wisconsin, Madison, Wisconsin

Neal L. Benowitz, M.D., Professor of Medicine, Chief, Division of
Clinical Pharmacology and Experimental Therapeutics, San Fran-
cisco General Hospital, University of California, San Francisco,
California

Thomas H. Brandon, M.S., Department of Psychology, University of
Wisconsin, Madison, Wisconsin

Richard F. Catalano, Ph.D., Research Assistant Professor, Center for
Social Welfare Research, School of Social Work, University of
Washington, Seattle, Washington

Larry D. Chait, Ph.D., Research Associate (Assistant Professor),
Department of Psychiatry, University of Chicago, Chicago, Illinois
Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera-
peutics, McGill University, Montreal, Quebec, Canada

ix


Richard R. Clayton, Ph.D., Professor, Department of Sociology,
University of Kentucky, Lexington, Kentucky
Allan C. Collins, Ph.D., Institute for Behavioral Genetics, School of
Pharmacy, University of Colorado, Boulder, Colorado
Thomas M. Cooper, D.D.S., Professor, Department of Community
Dentistry, University of Kentucky, Lexington, Kentucky
Lori A. Crane, M.P.H., Division of Cancer Control, Jonsson Compre-
hensive Cancer Center, University of California, Los Angeles,
California

Susan Curry, Ph.D., Center for Health Studies, Group Health
Cooperative of Puget Sound, Seattle, Washington
D. Layten Davis, Ph.D., Director, Tobacco and Health Research
Institute, University of Kentucky, Lexington, Kentucky
Ronald M. Davis, M.D., Director, Office on Smoking and Health,
Center for Health Promotion and Education, Centers for Disease
Control, Rockville, Maryland

Edward F. Domino, M.D., Professor, Department of Pharmacology,
University of Michigan, Ann Arbor, Michigan
John L. Egle, Jr., Ph.D., Department of Pharmacology/Toxicology,
Medical College of Virginia, Virginia Commonwealth University,
Richmond, Virginia

Joan Ershler, Ph.D., Research Associate, Mt. Sinai Medical Center,
Milwaukee, Wisconsin

Raymond Fleming, Ph.D., Assistant Professor, University of Wiscon-
sin-Milwaukee, Mt. Sinai Medical Center, Milwaukee, Wisconsin
Kathleen A. Fletcher, Ph.D., M.P.H., Consultant, The University of
Texas Health Science Center, Houston, Texas
Paul J. Fudala, Ph.D., Addiction Research Center, National Institute
on Drug Abuse, Baltimore, Maryland
C. Gary Gairola, Ph.D., University of Kentucky, Tobacco and Health
Research Institute, Lexington, Kentucky
David Gilbert, Ph.D., Department of Psychology, Southern Illinois
University, Carbondale, Illinois

Lewayne D. Gilchrist, Ph.D., Research Associate Professor, School of
Social Work, University of Washington, Seattle, Washington
Donna M. Goldberg, M.A., Annapolis, Maryland
Steven R. Goldberg, Ph.D., Preclinical Pharmacology Research
Branch, Addiction Research Center, National Institute on Drug
Abuse, Baltimore, Maryland

John Grabowski, Ph.D., Department of Psychiatry and Behavioral
Science, The University of Texas Health Science Center, Houston,
Texas

Neil E. Grunberg, Ph.D., Department of Medical Psychology, Uni-
formed Services University of the Health Sciences, Bethesda,
Maryland

X


Dorothy K. Hatsukami, Ph.D., Department of Psychiatry, University
of Minnesota, Minneapolis, Minnesota
J. David Hawkins, Ph.D., Professor, Center for Social Welfare
Research, School of Social Work, University of Washington,
Seattle, Washington

Jack E. Henningfield, Ph.D., Chief, Biology of Dependence and
Abuse Potential Assessment Laboratory, Addiction Research Cen-
ter, National Institute on Drug Abuse, Baltimore, Maryland.
Ronald I. Herning, Ph.D., Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland
Matthew Owen Howard, M.S., M.S.W., Research Assistant, Center
for Social Welfare Research, School of Social Work, University of
Washington, Seattle, Washington

John R. Hughes, M.D., Departments of Psychiatry, Psychology, and
Family Practice, University of Vermont, Burlington, Vermont
Edgar T. Iwamoto, Ph.D., Department of Pharmacology, College of
Medicine, University of Kentucky, Lexington, Kentucky
Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and
Hospital, School of Medicine, University of California, Los An-
geles, Veterans' Administration Medical Center, Brentwood Divi-
sion, Los Angeles, California

Robert C. Klesges, Ph.D., Associate Professor, Center for Applied
Psychological Research, Department of Psychology, Memphis
State University, Memphis, Tennessee
Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco
Use, Addiction Research Foundation, Professor of Psychology and
of Preventive Medicine and Biostatistics, University of Toronto,
Toronto, Ontario, Canada

Howard Leventhal, Ph.D., Professor and Chairman, Department of
Psychology, University of Wisconsin, Madison, Wisconsin
Edythe D. London, Ph.D., Chief, Neuropharmacology Laboratory,
Addiction Research Center, National Institute on Drug Abuse,
Baltimore, Maryland

Scott E. Lukas, Ph.D., Assistant Professor of Psychiatry (Pharmacol-
ogy), Harvard Medical School, Department of Psychiatry, Alcohol
and Drug Abuse Research Center, McLean Hospital, Belmont,
Massachusetts

Alfred C. Marcus, Ph.D., Associate Director, Division of Cancer
Control, Jonsson Comprehensive Cancer Center, University of
California, Los Angeles, California
Andrew W. Meyers, Ph.D., Professor, Center for Applied Psychologi-
cal Research, Department of Psychology, Memphis State Universi-
ty, Memphis, Tennessee

Thomas E. Novotny, M.D., Medical Epidemiologist, Office on Smok-
ing and Health, Center for Health Promotion and Education,
Centers for Disease Control, Rockville, Maryland

xi


Carol Tracy Orleans, Ph.D., Senior Investigator, Behavioral Medi-
cine and Director of Smoking Cessation Services, Division of
Cancer Control, Fox Chase Cancer Center, Philadelphia, Pennsyl-
vania

John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on
Smoking and Health, Center for Health Promotion and Education,
Centers for Disease Control, Rockville, Maryland
Ovide F. Pomerleau, Ph.D., Behavioral Medicine Program, Universi-
ty of Michigan, Department of Psychiatry, Ann Arbor, Michigan
Amelie G. Ramirez, M.P.H., Faculty Associate, The University of
Texas Health Science Center, Assistant Professor, Baylor College
of Medicine, Houston, Texas

Jed E. Rose, Ph.D., Veterans' Administration Medical Center,
Wadsworth and Brentwood Divisions, Los Angeles, California
J.A. Rosecrans, Ph.D., Department of Pharmacology, Medical Col-
lege of Virginia, Virginia Commonwealth University, Richmond,
Virginia

David P.L. Sachs, M.D., Director, Smoking Cessation Research
Institute, Palo Alto, California

Mary Anne Salmon, Ph.D., Research Associate, Health Services
Research Center, University of North Carolina, Chapel Hill, North
Carolina

Nina G. Schneider, Ph.D., Associate Research Psychologist, Depart-
ment of Psychiatry and Biobehavioral Sciences, UCLA School of
Medicine, Research Psychologist, Psychopharmacology Unit, Vet-
erans' Administration Medical Center, Brentwood Division, Los
Angeles, California

V.J. Schoenbach, Ph.D., Associate Professor, Department of Epide-
miology, Research Associate, Health Services Research Center,
University of North Carolina, Chapel Hill, North Carolina
Saul Shiffman, Ph.D., Associate Professor, Department of Psycholo-
gy, University of Pittsburgh, Pittsburgh, Pennsylvania
Victor J. Strecher, Ph.D., Research Associate, Health Services
Research Center, Assistant Professor, Department of Health
Education, University of North Carolina, Chapel Hill, North
Carolina

David M. Warburton, Professor, Department of Psychology, Univer-
sity of Reading, Whiteknights, Reading, United Kingdom
Elizabeth A. Wells, Ph.D., Post-Doctoral Fellow, Center for Social
Welfare Research, University of Washington, Seattle, Washington
Thomas Ashby Wills, Ph.D., Assistant Professor of Psychology,
Assistant Professor of Epidemiology and Social Medicine, Depart-
ment of Epidemiology and Social Medicine, Ferkauf Graduate
School of Psychology and Albert Einstein College of Medicine,
Bronx, New York

xii


Phillip P. Woodson, Dr.sc.nat., Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland

The editors acknowledge with gratitude the following distin-
guished scientists, physicians, and others who lent their support in
the development of this Report by coordinating manuscript prepara-
tion, contributing critical reviews of the manuscript, or assisting in
other ways.

Leo G. Abood, Ph.D., Department of Pharmacology, University of
Rochester Medical Center, Rochester, New York
John S. Baer, Ph.D., Department of Psychology, University of
Washington, Seattle, Washington
Timothy B. Baker, Ph.D., Department of Psychology, University of
Wisconsin, Madison, Wisconsin

Claudia R. Baquet, M.D., M.P.H., Chief, Special Populations Studies
Branch, Division of Cancer Prevention and Control, National
Cancer Institute, Bethesda, Maryland
Glen Bennett, M.P.H., Field Studies Advisor, Office of Prevention,
Education, and Control, National Heart, Lung, and Blood Insti-
tute, Bethesda, Maryland

George E. Bigelow, Ph.D., Associate Professor of Behavioral Biology,
Director, Behavioral Pharmacology Research Unit, Department of
Psychiatry and Behavioral Sciences, The Johns Hopkins Universi-
ty School of Medicine, Baltimore, Maryland
Clarice Brown, M.S., Data Analyst, Office of Prevention, Education,
and Control, National Heart, Lung, and Blood Institute, Bethesda,
Maryland

David M. Burns, M.D., Associate Professor of Medicine, Division of
Pulmonary and Critical Care Medicine, University of California
Medical Center, San Diego, California
Donald R. Cherek, Ph.D., Department of Psychiatry and Behavioral
Sciences, Mental Sciences Institute, The University of Texas
Health Science Center, Houston, Texas
Paul B.S. Clarke, Ph.D., Department of Pharmacology and Thera-
peutics, McGill University, Montreal, Quebec, Canada
Ro Nemeth-Coslett, Ph.D., Psychologist, Prevention Research
Branch, Division of Clinical Research, National Institute on Drug
Abuse, Rockville, Maryland

Thomas J. Crowley, M.D., University of Colorado Health Sciences
Center, Denver, Colorado

Joseph W. Cullen, Ph.D., Deputy Director, Division of Cancer
Prevention and Control, National Cancer Institute, Bethesda,
Maryland

K. Michael Cummings, Ph.D., M.P.H., Research Scientist, Depart-
ment of Cancer Control and Epidemiology, Roswell Park Memorial
Institute, Buffalo, New York

. .
x111


Susan Curry, Ph.D., Center for Health Studies, Group Health
Cooperative of Puget Sound, Seattle, Washington
Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland
Sir Richard Doll, University of Oxford, Oxford, England
Manning Feinleib, M.D., Dr.P.H., Director, National Center for
Health Statistics, Centers for Disease Control, Hyattsville, Mary-
land

William H. Foege, M.D., Executive Director, The Carter Center of
Emory University, Atlanta, Georgia
Richard R. Frecker, M.D., Ph.D., Head, Biomedical Research,
Department of Pharmacology, Addiction Research Foundation,
Toronto, Ontario, Canada

K.H. Ginzel, Ph.D., Professor, Department of Pharmacology and
Interdisciplinary Toxicology, University of Arkansas for Medical
Sciences, Little Rock, Arkansas
Russell E. Glasgow, Ph.D., Oregon Research Institute, Eugene,
Oregon

Nancy P. Gordon, Sc.D., Behavioral Scientist, Division of Research,
Kaiser Permanente Medical Group, Oakland, California
Roland R. Griffiths, The Johns Hopkins University School of
Medicine, Baltimore, Maryland

Ellen R. Gritz, Ph.D., Director, Division of Cancer Control, Jonsson
Comprehensive Cancer Center, University of California, Los
Angeles, California

Sharon M. Hall, Ph.D., Professor, Department of Psychiatry, Center
for Social and Behavioral Sciences, University of California, San
Francisco, California

Louis S. Harris, Ph.D., Senior Science Advisor, National Institute on
Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administra-
tion, Rockville, Maryland

Ronald I. Herning, Ph.D., Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland
Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Insti-
tute, Valhalla, New York

Leo Hollister, M.D., Medical Director, Harris County Psychiatry
Center, Houston, Texas

Enid Hunkeler, Senior Investigator, Kaiser Permanente Medical
Care Program, Oakland, California
Peyton Jacob III, Ph.D., Division of Clinical Pharmacology, San
Francisco General Hospital, University of California, San Francis-
co, California

Jerome Jaffe, M.D., Director, Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland
Murray E. Jarvik, M.D., Ph.D., The Neuropsychiatric Institute and
Hospital, School of Medicine, University of California, Los An-

xiv


geles, and Veterans' Administration Medical Center West LOS
Angeles, Brentwood Division, Los Angeles, California
Martin Jarvis, M.Phil., Senior Lecturer, Addiction Research Unit,
Institute of Psychiatry, London, England
Chris-Ellen Johanson, Ph.D., Department of Psychiatry, Pritzker
School of Medicine, University of Chicago Drug Abuse Research
Center, Chicago, Illinois

Reese T. Jones, Ph.D., Department of Psychiatry, University of
California School of Medicine, San Francisco, California
Kenneth J. Kellar, Ph.D., Department of Pharmacology, Georgetown
University Medical Center, Washington, D.C.
Lynn T. Kozlowski, Ph.D., Head, Behavioral Research on Tobacco
Use, Addiction Research Foundation, Toronto, Ontario, Canada
Richard J. Lamb, Ph.D., Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland
Charles L. LeMaistre, M.D., President, University of Texas Systems
Cancer Center, Houston, Texas

Claude Lenfant, M.D., Director, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Howard Leventhal, Ph.D., Professor of Psychology, University of
Wisconsin, Madison, Wisconsin

Edward Lichtenstein, Ph.D., Oregon Research Institute, Eugene,
Oregon

Donald Ian Macdonald, M.D., Administrator, Alcohol, Drug Abuse,
and Mental Health Administration, Rockville, Maryland
G. Alan Marlatt, Ph.D., Professor of Psychology, University of
Washington, Seattle, Washington
William R. Martin, M.D., Chairman, Department of Pharmacology,
University of Kentucky College of Medicine, Lexington, Kentucky
James 0. Mason, M.D., Dr.P.H., Director, Centers for Disease
Control, Atlanta, Georgia

J. Michael McGinnis, M.D., Deputy Assistant Secretary (Disease
Prevention and Health Promotion), Washington, D.C.
A. Thomas McLellan, Ph.D., Substance Abuse Treatment Research
Center, Philadelphia Veterans' Administration Medical Center
and The University of Pennsylvania, Philadelphia, Pennsylvania
Nancy K. Mello, Ph.D., Alcohol and Drug Abuse Research Center,
McClean Hospital, Belmont, Massachusetts
Gregory J. Morosco, Ph.D., M.P.H., Smoking Education Program
Coordinator, National Heart, Lung, and Blood Institute, Bethesda,
Maryland

Joseph P. Mulholland, Ph.D., Bureau of Economics, Federal Trade
Commission, Washington, D.C.

Herbert W. Nickens, M.D., M.A., Director, Office of Minority Health,
Public Health Service, Washington, D.C.

xv


Richard Peto, M.A., M.Sc., Imperial Cancer Research Fund, Cancer
Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe
Infirmary, University of Oxford, Oxford, England
Roy W. Pickens, Ph.D., Director, Division of Clinical Research,
National Institute on Drug Abuse, Rockville, Maryland
John P. Pierce, MSc., Ph.D., Chief, Epidemiology Branch, Office on
Smoking and Health, Center for Health Promotion and Education,
Centers for Disease Control, Rockville, Maryland
John M. Pinney, Executive Director, Institute for the Study of
Smoking Behavior and Policy, John F. Kennedy School of Govern-
ment, Harvard University, Cambridge, Massachusetts
Michael R. Polen, M.A., Research Associate, Division of Research,
Kaiser-Permanente Medical Group, Oakland, California
William Pollin, M.D., Former Director, National Institute on Drug
Abuse, Bethesda, Maryland

David C. Ramsey, M.P.H., Health Educator, Division of Health
Education, Center for Health Promotion and Education, Centers
for Disease Control, Atlanta, Georgia
Everett R. Rhoades, M.D., Assistant Surgeon General and Director,
Indian Health Service, Rockville, Maryland
M.A.H. Russell, F.R.C.P., Addiction Research Unit, Institute of
Psychiatry, University of London, London, England
Charles R. Schuster, Ph.D., Director, National Institute on Drug
Abuse, Rockville, Maryland

Burt Sharpe, M.D., Hennepin County Medical Center, Department of
Medicine, Minneapolis, Minnesota
Donald R. Shopland, Public Health Advisor, Smoking, Tobacco, and
Cancer Program, National Cancer Institute, Bethesda, Maryland
Jerome E. Singer, Ph.D., Medical Psychology, Uniformed Services
University of the Health Sciences, Bethesda, Maryland
Maxine L. Stitzer, Ph.D., Associate Professor, Behavioral Biology,
The Johns Hopkins School of Medicine, Behavioral Pharmacology
Research, Francis Scott Key Medical Center, Baltimore, Maryland
David N. Sundwall, M.D., Assistant Surgeon General and Adminis-
trator, Health Resources and Services Administration, Rockville,
Maryland

Dennis D. Tolsma, M.P.H., Director, Center for Health Promotion
and Education, Centers for Disease Control, Atlanta, Georgia
Frederick L. Trowbridge, M.D., Director, Division of Nutrition,
Center for Health Promotion and Education, Centers for Disease
Control, Atlanta, Georgia

Frank J. Vocci, Jr., Ph.D., Acting Chief, Drug Abuse Staff, Center for
Drug Evaluation and Research, Food and Drug Administration,
Washington, DC

Ronald W. Wilson, M.A., National Center for Health Statistics,
Centers for Disease Control, Hyattsville, Maryland

xvi


Roy A. Wise, Ph.D., Department of Psychology, Concordia Universi-
ty, Montreal, Quebec, Canada
Faye Wright, Center for Applied Psychological Research, Depart-
ment of Psychology, Memphis State University, Memphis, Tennes-
see

Ernst L. Wynder, M.D., President, American Health Foundation,
New York, New York

James B. Wyngaarden, M.D., Director, National Institutes of Health,
Bethesda, Maryland

Tomoji Yanagita, M.D., Ph.D., Preclinical Research Laboratories,
Central Institute for Experimental Animals, Kawasaki, Japan
Frank E. Young, M.D., Commissioner, Food and Drug Administra-
tion, Rockville, Maryland

The editors also acknowledge the contributions of the following
staff members and others who assisted in the preparation of this
Report.

Margaret Anglin. Secretary, Office on Smoking and Health, Rock-
ville, Maryland

Charles Appiah, Project Clerk. Smoking and Health Project,. The
Circle, Inc., McLean, Virginia

John L. Bagrosky, Associate Director for Program Operations, Office
on Smoking and Health, Rockville, Maryland
Sonia Balakirsky, Secretary, Office on Smoking and Health, Rock-
ville, Maryland

Carol Bean, Associate Project Director, Smoking and Health Project,
The Circle, Inc., McLean, Virginia
Tamara Blair, Production Coordinator, Information Management
Department, ATLIS Federal Services, Inc., Rockville, Maryland
Catherine E. Burckhardt, Editorial Assistant, Office on Smoking and
Health, Rockville, Maryland

Gayle Christman, Word Processing Specialist, Smoking and Health
Project, The Circle, Inc., McLean, Virginia
Carol K. Cummings, Secretary, Office on Smoking and Health,
Rockville, Maryland

Stephanie D. DeVoe, Programmer, Information Systems Depart-
ment, ATLIS Federal Services, Inc., Rockville, Maryland
Michael C. Fiore, M.D., M.P.H., Medical Epidemiologist, Office on
Smoking and Health, Rockville, Maryland
David Fry, Editor, Smoking and Health Project, The Circle, Inc.,
McLean, Virginia

Lynn Funkhauser, Word Processing Specialist, Smoking and Health
Project, The Circle, Inc., McLean, Virginia
Mary Gardner, Senior Editor, Smoking and Health Project, The
Circle, Inc., McLean, Virginia

xvii


Amy Garson, M.P.H. student, Office on Smoking and Health,
Rockville: Maryland

-4rnetta G. Glover, Secretary, Office on Smoking and Health,
Rockville, Maryland

William Groskopf, Library Acquisitions Specialist, Information
Management Department, ATLIS Federal Services, Inc., Rock-
ville, Maryland

Evridiki Hatziandreu, M.D., M.P.H., Epidemic Intelligence Service
Officer, Office on Smoking and Health, Rockville, Maryland
Susan A. Hawk, Ed.M., M.S., Chief, Technical Information Center,
Office on Smoking and Health, Rockville, Maryland
Patricia E. Healy, Technical Information Specialist, Office on
Smoking and Health, Rockville, Maryland
Terri L. Henry, Clerk-Typist, Office on Smoking and Health.
Rockville, Maryland

Timothy K. Hensley, Technical Publications Writer, Office on
Smoking and Health, Rockville, Maryland
Shirley K. Hickman, Data Entry Operator, Information Manage-
ment Department, ATLIS Federal Services, Inc., Rockville, Mary-
land

Robert S. Hutchings, Associate Director for Information and Pro-
gram Development, Office on Smoking and Health, Rockville,
Maryland

Karen Jacob, Senior Editor, Smoking and Health Project, The Circle,
Inc., McLean, Virginia

Sheila Jones, Word Processing Specialist, Smoking and Health
Project, The Circle, Inc., McLean, Virginia
Rick Keir, Senior Editor, Smoking and Health Project, The Circle,
Inc., McLean, Virginia

Julie Kurz, Graphics Specialist, Information Management Depart-
ment, ATLIS Federal Services, Inc., Rockville, Maryland
Diana Lord, Research Assistant, Department of Medical Psychology,
Uniformed Services University of the Health Sciences, Bethesda,
Maryland

Gerri E. Mast, Secretary, Center for Health Promotion and Educa-
tion, Centers for Disease Control, Atlanta, Georgia
Judy J. Mast, Secretary, Center for Health Promotion and Educa-
tion, Centers for Disease Control, Atlanta, Georgia
Dixie McGough, Program Manager, Information Management De-
partment, ATLIS Federal Services, Inc., Rockville, Maryland
Paul G. McGovern, Ph.D., Postdoctoral Research Associate, Smoking
Research Group, Department of Psychology, Iowa State Universi-
ty, Ames, Iowa

Dan McLaughlin, Editorial Assistant, Smoking and Health Project,
The Circle, Inc., McLean, Virginia

. . .
xv111


Nancy Miltenberger, Editor. Smoking and Health Project, The
Circle, Inc., McLean, Virginia

Cathie O'Donnell, Senior Editor, Smoking and Health Project, The
Circle, Inc., McLean, Virginia

Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville,
Maryland

Russell D. Peek, Library Acquisitions Specialist, Information Man-
agement Department, ATLIS Federal Services, Inc., Rockville,
Mar.yland

Mary B. Pfeiffer, M.L.S., Librarian, Addiction Research Center,
National Institute on Drug Abuse, Baltimore, Maryland
Margaret E. Pickerel, Public Information and Publications Special-
ist, Office on Smoking and Health, Rockville, Maryland
Renate Phillips, Desktop Publishing/Graphic Artist, Smoking and
Health Project, The Circle, Inc., McLean, Virginia
Karen Sherman, Production Assistant, Information Management
Department, ATLIS Federal Services, Inc., Rockville, Maryland
Linda R. Spiegelman. Administrative Officer, Office on Smoking and
Health, Rockville, Maryland

Tamara Shipp, Publications Assistant, Smoking and Health Project,
The Circle, Inc., McLean, Virginia
Evelyn L. Swarr, Systems Management Projects Supervisor, Infor-
mation Systems Department, ATLIS Federal Services, Inc., Rock-
ville, Maryland

Patricia Y. Thomas, Secretary, Addiction Research Center, National
Institute on Drug Abuse, Baltimore, Maryland
Daniel R. Tisch, Project Director, Smoking and Health Project, The
Circle, Inc., McLean, Virginia

Louise G. Wiseman, Technical Information Specialist, Office on
Smoking and Health, Rockville, Maryland

xix


TABLE OF CONTENTS

Foreword ................................................................. i


Preface .................................................................. iii

Acknowledgments .................................................... ix

I. Introduction, Overview, Summary, and
  Conclusions . . . . . . . . . . . . . . . . . . ..**............................... 1

II. Nicotine: Pharmacokinetics, Metabolism, and Phar-
macodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

III. Nicotine: Sites and Mechanisms of Actions.. ........ .75


IV. Tobacco Use as Drug Dependence ..................... 145

V. Tobacco Use Compared to Other Drug
  Dependencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

VI. Effects of Nicotine That May Promote Tobacco
  Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

$11. Treatment of Tobacco Dependence.. . . . . . . . . . . . . . . . . . . .459

Appendix A: Trends in Tobacco Use in the United
       States . . . . . , . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . .561

Appendix B: Toxicity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . 619

xxi


CHAPTER I

INTRODUCTION, OVERVIEW,
SUMMARY, AND CONCLUSIONS


CONTENTS

Introduction ............................................................ 5
Development and Organization of this Report ......... 5

Overview ................................................................ 6

Major Conclusions .................................................... 9

                                               .__-
Brief History Relevant to this Report .......................... 9

Chapter Conclusions ............................................... .13
  Chapter II:  Nicotine: Pharmacokinetics, Metabo-
         lism, and Pharmacodynamics ........... .13
  Chapter III: Nicotine: Sites and Mechanisms of
          Actions  ........................................ ,14
  Chapter IV: Tobacco Use as Drug Dependence.. ... .14
  Chapter V:  Tobacco Use Compared to Other Drug
         Dependencies ................................. .15
Chapter VI: Effects of Nicotine That May Promote
           Tobacco Use .................................. .15
Chapter VII: Treatment of Tobacco Dependence .... .15
  Appendix A: Trends in Tobacco Use in the United
           States .......................................... .16
  Appendix B: Toxicity of Nicotine  ....................... .16

References ............................................................ .18

3


Introduction
Development and Organization of this Report
This Report was developed by the Office on Smoking and Health,
Center for Health Promotion and Education, Centers for Disease
Control, Public Health Service of the U.S. Department of Health and
Human Services as part of the Department's responsibility, under
Public Law 91-222, to report new and current information on
smoking and health to the United States Congress.
The scientific content of this Report reflects the contributions of
more than 50 scientists representing a wide variety of relevant
disciplines. These experts, known for their understanding of and
work in specific content areas, prepared manuscripts for incorpora-
tion into this Report. The Office on Smoking and Health and its
consultants edited and consolidated the individual manuscripts into
appropriate chapters. These draft chapters were subjected to an
extensive outside peer review (see Acknowledgments for individuals
and their affiliations) whereby each chapter was reviewed by up to
11 experts. Based on the comments of these reviewers, the chapters
were revised and the entire volume was assembled. This revised
edition of the Report was resubjected to review by 20 distinguished
scientists inside and outside the Federal Government, both in this
country and abroad. Parallel to this review, the entire Report was
also submitted for review to 12 institutes and agencies within the
U.S. Public Health Service. The comments from the senior scientific
reviewers and the agencies were used to prepare the final volume of
this Report.
This Report contains a Foreword by the Assistant Secretary for
Health, a Preface by the Surgeon General of the U.S. Public Health
Service, and the following chapters and appendices:

  Chapter I.  Introduction. Overview, Summary, and Conclu-
           sions
Chapter II. Nicotine: Pharmacokinetics, Metabolism, and
        Pharmacodynamics
Chapter III. Nicotine: Sites and Mechanisms of Actions
Chapter IV. Tobacco Use as Drug Dependence
Chapter V. Tobacco Use Compared to Other Drug
         Dependencies
Chapter VI. Effects of Nicotine That May Promote Tobacco
          Use
Chapter VII. Treatment of Tobacco Dependence
Appendix A. Trends in Tobacco Use in the United States
Appendix B. Toxicity of Nicotine


Overview

This Report of the Surgeon General on tobacco and health focuses
on the pharmacologic basis of tobacco addiction. Previous Surgeon
General's Reports have reviewed the medical and scientific evidence
establishing that cigarette smoking and tobacco use in other forms
are deleterious to health. Several reports emphasized particular
diseases (e.g., 1982 Report on cancer (US DHHS 1982), 1983 Report
on cardiovascular disease (US DHHS 1983a), 1984 Report on chronic
obstructive lung disease (US DHHS 1984a)); some reports concentrat-
ed on specific populations (e.g., 1980 Report on women (US DHHS
1980)); and some reports dealt with particular aspects of smoking
(e.g., 1986 Report on involuntary smoking (US DHHS 1986a)). These
reports have been important because so many individuals engage in
a behavior that causes morbidity and premature mortality.

The present Report addresses a central issue of the tobacco and
health problem: Why do people smoke and in other ways consume
tobacco products? Specifically, this Report reviews the pharmacolog-
ic basis of the disease-producing and life-threatening behavior of
tobacco use. Psychological and social factors are also important
influences on tobacco use, but a detailed review of these factors is
beyond the scope of this Report. Reviews of this literature include
previous reports of the Surgeon General (US DHEW 1979; US DHHS
1980, 1982, 1983a, 1984a), research monographs from the National
Institute on Drug Abuse (NTDA) (Jarvik et al. 1977; Krasnegor 1978,
1979a,b,c; Grabowski and Bell 1983), and articles by scientists who
study tobacco use and nicotine (Russell 1971, 1976; Gritz 1980;
Henningfield 1984).

This Report reviews evidence that tobacco use is addicting and
that nicotine is the active pharmacologic agent of tobacco that causes
this addictive behavior. Previous Surgeon General's Reports have
focused on evidence that cigarette smoking and tobacco use are
health hazards. Now that those relationships are well-documented
and well-known, this Report addresses addictive properties of
cigarette smoking and tobacco use in order to help develop more
effective prevention and cessation programs.

This Report topic is particularly timely because of recent advances
and extensive data gathered in the 1980s relevant to the issue of
tobacco addiction. Since the early 1900s scientific literature and
historical anecdotes have provided evidence that tobacco use is a
form of drug addiction. In the 1970s however, research efforts
increased considerably on various aspects of tobacco addiction,
including nicotine pharmacokinetics, pharmacodynamics, self-ad-
ministration, withdrawal, dependence, and tolerance. In addition,
advances in the neurosciences have begun to reveal effects of
nicotine in the brain and body that may help to explain why tobacco
use is reinforcing and difficult to give up. These issues are addressed

6


in this Report. Finally, recent developments in the use of nicotine
replacement in smoking cessation emphasize the importance of
pharmacologic aspects of cigarette smoking.

Concepts of drug addiction or drug dependence are discussed in
detail in Chapters IV and V. It is useful to begin this Report with a
brief summary of main points about drug dependence that provide
the foundation for the findings of the Report.

The terms "drug addiction" and "drug dependence" are scientifi-
cally equivalent: both terms refer to the behavior of repetitively
ingesting mood-altering substances by individuals. The term "drug
dependence" has been increasingly adopted in the scientific and
medical literature as a more technical term, whereas the term "drug
addiction" continues to be used by NIDA and other organizations
when it is important to provide information at a more general level.
Throughout this Report, both terms are used and they are used
synonymously.

The main conclusions of the Report are based upon concepts of
drug dependence that have been developed by expert committees of
the World Health Organization, as well as in publications of NIDA
and the American Psychiatric Association. These concepts were used
to develop a set of criteria to determine whether tobacco-delivered
nicotine is addicting. The criteria for drug dependence include
primary and additional indices and are summarized below.

CRITERIA FOR DRUG DEPENDENCE

Primary Criteria
. Highly controlled or compulsive use
. Psychoactive effects
. Drug-reinforced behavior

Additional Criteria

. Addictive behavior often involves:
  -stereotypic patterns of use
  -use despite harmful effects
  -relapse following abstinence
  -recurrent drug cravings
. Dependence-producing drugs often produce:
  -tolerance
  -physical dependence
  -pleasant (euphoriantl ef'fects

The primary crit.eria listed above are sufficient to define drug
dependence. Highly controlled or compulsive use indicates that drug-


seeking and drug-taking behavior is driven by strong, often irresisti-
ble urges. It can persist despite a desire to quit or even repeated
attempts to quit. Such behavior is also referred to as "habitual"
behavior. To distinguish drug dependence from habitual behaviors
not involving drugs, it must be demonstrated that a drug with
psychoactive (mood-altering) effects in the brain enters the blood
stream. Furthermore, drug dependence is defined by the occurrence
of drug-motivated behavior; therefore, the psychoactive chemical
must be capable of functioning as a reinforcer that can directly
strengthen behavior leading to further drug ingestion.

Additional criteria are often used to help characterize drug
dependence. Several are associated with the drug-taking behavior
itself': (1) the behavior may develop into regular temporal and
physical patterns of use (repetitive and stereotypic); (2) drug use may
persist despite adverse physical, psychological, or social conse-
quences; (3) quitting episodes are often followed by resumption of
drug use (relapse); (4) urges (cravings) to use the drug may be
recurrent and persistent, especially during drug abstinence. Similar-
ly, several common effects of dependence-producing drugs can
strengthen their control over behavior and increase the likelihood of
harm by contributing to the regularity and overall level of drug
intake: (1) diminished responsiveness (tolerance) to the effects of a
drug occurs, and may be accompanied by increased intake over time;
(2) abstinence-associated withdrawal reactions (due to physical
dependence) can motivate further drug intake; (3) effects that are
considered pleasant (euphoriant) to the drug user can be provided by
the drug itself. Dependence-producing drugs can also produce effects
that individuals find useful. For example, many addicting drugs
have therapeutic uses in medical treatments of various disorders.
Most medically approved drugs that are addicting, however, are
generally only available by prescription. Effects of a drug considered
by the individual to be useful can promote initiation of drug use,
strengthen the addiction, and contribute to relapse following cessa-
tion of use.

Tobacco and nicotine are considered in the Report in light of the
above criteria. In brief, the organization of the Report is as follows:
review of evidence that tobacco use is accompanied by orderly
patterns of uptake of nicotine in the body and brain resulting in the
development of tolerance (Chapter II); review of how effects of
nicotine in the brain and the rest of the body are chemically
mediated (Chapter 1111; review of the evidence that tobacco is
addicting and that nicotine is an addicting drug (Chapter IV);
comparison of tobacco use with other addictions and of nicotine with
other addicting drugs (Chapter VI: review of possible effects of
nicotine that may promote the use of tobacco and present impedi-
ments to quitting smoking (Chapter VII; review of strategies for

8


helping people to achieve and maintain tobacco abstinence (Chapter
VII). In addition, appendices are included that summarize informa-
tion regarding trends in tobacco use (Appendix A) and information
regarding the toxicity of nicotine itself (Appendix BI. A summary of
the main findings of the Report follows.

Major Conclusions

   1.  Cigarettes and other forms of tobacco are addicting.

2.  Nicotine is the drug in tobacco that causes addiction.

3.  The pharmacologic and behavioral processes that
  determine tobacco addiction are similar to those that
determine addiction to drugs such as heroin and
  cocaine.

Brief History Relevant to this Report

Tobacco products have been used for centuries. The tobacco plant
was native to the New World. The oldest cited evidence of tobacco
use appears on a Mayan stone carving dated from 600 to 900 A.D.
There are reports of tobacco smoking in Christopher Columbus'
diary in 1492; reports of tobacco smoking appear in the logs of other
European explorers of the New World in the 16th century. Since the
colonial period, tobacco has been an integral part of the American
economy (Robert 19491.

Tobacco use permeated the New World and quickly spread
throughout the rest of the world during the 16th and 17th centuries.
As use of tobacco products spread, so did controversy over the effects
of these products. Throughout history, while some persons extolled
the virtues of tobacco (including numerous alleged medicinal uses),
others condemned its use. George Washington is attributed with
exhorting the home front during the Revolutionary War, "If you
can't send money, send tobacco." In contrast, Dr. Benjamin Rush
condemned tobacco use in his 1798 book Essa,vs. The controversy
continued into the 19th century with no convincing scientific or
medical evidence to support either position (Robert 1949).

In 1856-57 the British medical journal Lancet published opinions
of 50 physicians on tobacco use. Many opponents attributed in-
creased crime, nervous paralysis, loss of intellectual abilities, and
visual impairment to tobacco use-all of these claims lacked
convincing evidence. In restating the main arguments of the tobacco
proponents, the Lancet editors wrote that tobacco use "...must have
some good or at least pleasurable effects; that, if its evil effects were

9


so dreadful as stated the human race would have ceased to exist"
(Lancet 1857).

While the health-promoting and health-damaging effects of tobac-
co products were being debated throughout the 17th and 18th
centuries, scientists were trying to determine the chief active
ingredient in tobacco. In the early 1800s the oily essence of tobacco
was discovered by Cerioli and by Vauquelin. This active substance
was named "Nicotianine," after Jean Nicot, who sent tobacco seeds
from Portugal to the French court at the end of the 16th century. In
1828, Posselt and Reimann at the University of Heidelberg isolated
the pure form of Nicotianine and renamed it, "Nikotin." The
chemical's empirical formula, C10H,4N2, was determined in the
184Os, and "nicotine" was synthesized in the 1890s (Robert 1949).

Since the late 1800s research on the pharmacologic actions of
nicotine has contributed substantially to basic information about the
nervous system (Kharkevich 1980; Volle 1980). The classic work by
Langley and Dickinson (18891 on nicotine's effects in autonomic
ganglia led to the postulates that chemicals transmit information
between neurons and that there are receptors on cells that respond
functionally to stimulation by specific chemicals. As early as the
1920s and 1930s some investigators were concluding that nicotine
was responsible for the compulsive use of tobacco products (Arm-
strong-Jones 1927; Dorsey 1936; Lewin 1931). Johnston (1942)
concluded that, "smoking tobacco is essentially a means of adminis-
tering nicotine, just as smoking opium is a means of administering
morphine."

Throughout the 20th century, research has continued to investi-
gate the role of nicotine in tobacco use. The 1964 Report of the
Surgeon General's Advisory Committee on Smoking and Health (US
PHS 19641 held that: "The habitual use of tobacco is related
primarily to psychological and social drives, reinforced and perpetu-
ated by the pharmacologic actions of nicotine on the central nervous
system. Nicotine-free tobacco or other plant materials do not satisfy
the needs of those who acquire the tobacco habit." The 1964 Report,
relying upon a distinction (that is no longer made) between
"habituating" and "addicting" drugs. asserted that tobacco was
habituating and not addicting. The distinction in 1964 between
habituating drugs iincluding cocaine and amphetamines) and addict-
ing drugs (including opiates and barbiturates) was based on: (1)
whether the drug produced clear physical dependence; (2) whether
damage was mainly to the individual user (habituating drugs) or to
society (addicting drugs); and (3) the strength of the habitual
behavior that developed. There was no question at the time of the
1964 Report that nicotine was the critical pharmacologic agent for
tobacco use, but its role was then considered to be more similar to
cocaine and amphetamines than to opiates and barbiturates. Later

10


in 1964 the World Health Organization dropped this semantic
distinction between habituating and addicting drugs because it was
recognized that habitual use could be as strongly developed for
cocaine as for morphine. that social damage generally accompanied
personal damage, and that behavioral characteristics of drug use
could be similar for the so-called habituating and addicting drugs. In
an effort to shift the focus to dependent patterns of behavior and
away from moral and social issues associated with the term
addiction, the term dependence was recommended.

It is now clear that even by the earlier distinction in nomencla-
ture, cigarettes and other forms of tobacco are addicting and actions
of nicotine provide the pharmacologic basis of tobacco addiction. The
term "dependence producing" may also be used to describe cigarettes
and other forms of tobacco use, analogous to actions of other drugs
(e.g., opiates, cocaine). Since 1964, considerable additional evidence
has been compiled that substantiates these conclusions. The present
Report reviews this information and the relevant literature.

Previous Surgeon General's Reports provided current reviews of
the health consequences of cigarette smoking particularly relevant
to public health. For example, despite the accumulating evidence, in
the early 1960s there was little recognition by the public of the
health hazards of smoking. Each Report examined specific informa-
tion considered to be important for public dissemination. A brief
review of topics addressed in these reports provides the background
for the present Report.

In the late 195Os, the U.S. Public Health Service, the National
Cancer Institute, the National Heart Institute, the American Cancer
Society, and the American Heart Association appointed a study
group to examine the available evidence on smoking and health.
This study group concluded that excessive cigarette smoking is a
causative factor in lung cancer.

In 1962, Surgeon General Luther Terry established an advisory
committee on smoking and health. This committee released its
Report on January 11, 1964, concluding that cigarette smoking is a
cause of lung cancer in men and a suspected cause of lung cancer in
women, and increased the risk of dying from pulmonary emphysema.
The next Report was issued in 1967 (US PHS 1968a) and stated that
"the case for cigarette smoking as the principal cause of lung cancer
is overwhelming." Further, the 1967 Report concluded that: "There
is an increasing convergence of many types of evidence . . . which
strongly suggests that cigarette smoking can cause death from
coronary heart disease." The 1967 Report also concluded that
"Cigarette smoking is the most important of the causes of chronic
non-neoplastic bronchopulmonary disease in the United States."

The 1968 and 1969 Reports (US PHS 1968b, 1969) strengthened
the conclusions reached in 1967. The 1971 Report provided a detailed

11


review of the evidence to date regarding health consequences of
smoking (US DHEW 1971). The subsequent reports (1972 to 1976)
continued to review the increasing evidence associating cigarette
smoking with many health hazards. The 1972 Report also discussed
involuntary or passive smoking (US DHEW 1972). The 1973 Report
included some data on the health hazards of smoking pipes and
cigars (US PHS 1973). The 1975 Report updated information on the
health effects of involuntary or passive smoking (US DHEW 1975).
The combined 1977-78 Report discussed smoking-related problems
unique to women (US DHEW 1978).
At the time of its release, the 1979 Report was the most
comprehensive review by a Surgeon General's Report of the health
consequences of smoking, smoking behavior, and smoking control. In
addition to providing a thorough review of the health consequences
of smoking, the 1979 Report discussed the health consequences of
using forms of tobacco other than cigarettes (pipes, cigars, and
smokeless tobacco). Moreover, the 1979 Report expanded the scope of
the previous reports and examined behavioral, pharmacologic, and
social factors influencing the initiation, maintenance, and cessation
of cigarette smoking. Relevant to the topic of the present Report, the
1979 Report concluded that "it is no exaggeration to say that
smoking is the prototypical substance-abuse dependency and that
improved knowledge of this process holds great promise for preven-
tion of risk." Since the release of the 1979 Report, each subsequent
Report has focused on a specific population or setting (women in
1980 (US DHHS 19801, the workplace in 1985 (US DHHS 1985)), a
specific topic (health effects of low-tar and low-nicotine cigarettes in
1981 (US DHHS 19811, involuntary smoking in 1986 (US DHHS
1986a)), or a specific disease (cancer in 1982 (US DHHS 19821,
cardiovascular diseases in 1983 (US DHHS 1983aL chronic obstruc-
tive lung disease in 1984 (US DHHS 1984al).
In addition to the previous Surgeon General's Reports, several
other developments and publications provide relevant background
for the present Report. For example, numerous monographs pre-
pared in the 1970s by the National Institute on Drug Abuse (NIDA)
considered tobacco use as a form of drug dependence. In 1980, the
American Psychiatric Association, in its Diagnostic and Statistical
Manual of Mental Disorders, included tobacco dependence as a
substance abuse disorder and tobacco withdrawal as an organic
mental disorder (APA 1980). The 1987 revised edition of this manual
tAPA 1987), in recognition of the role of nicotine, changed "tobacco
withdrawal" to "nicotine withdrawal." In 1982, the Director of NIDA
testified to Congress that the position of NIDA was that tobacco use
could lead to dependence and that nicotine was a prototypic
dependence-producing drug. In a 1983 publication, "Why People
Smoke Cigarettes," the U.S. Public Health Service supported this


position of NIDA regarding tobacco and nicotine (US DHHS 1983133.
In the 1984 NIDA Triennial Report to Congress, nicotine was labeled
a prototypic dependence-producing drug and the role of nicotine in
tobacco use was considered to be analogous to the roles of morphine,
cocaine, and ethanol, in the use of opium, coca-derived products, and
alcoholic beverages, respectively (US DHHS 1984b3. In 1986, a
consensus conference of the National Institutes of Health and the
Report of the Advisory Committee to the Surgeon General on the
health consequences of using smokeless tobacco concluded that
smokeless tobacco can be addicting and that nicotine is a depen-
dence-producing (i.e., addicting) drug (US DHHS 1986b).

The present Report is the 20th such report issued by the Public
Health Service on the health consequences of tobacco use. The
deleterious effects of cigarette smoking are now well known.
Therefore, this Report focuses on pharmacologic information to help
understand why people smoke. Such information will assist health
professionals in developing effective strategies to prevent initiation
and to promote cessation. The literature reviewed in this Report
indicates that tobacco use is an addictive behavior. It is the purpose
of this Report to thoroughly review the relevant literature.

Chapter Conclusions

In addition to the three overall conclusions of this Report, there
are many other substantive conclusions. These points are listed
under the appropriate Chapter and Appendix headings.

Chapter II: Nicotine: Pharmacokinetics, Metabolism, and Phar-
macodynamics

1. All tobacco products contain substantial amounts of nicotine
and other alkaloids. Tobaccos from low-yield and high-yield
cigarettes contain similar amounts of nicotine.
2. Nicotine is absorbed readily from tobacco smoke in the lungs
and from smokeless tobacco in the mouth or nose. Levels of
nicotine in the blood are similar in magnitude in people using
different forms of tobacco. With regular use, levels of nicotine
accumulate in the body during the day and persist overnight.
Thus, daily tobacco users are exposed to the effects of nicotine
for 24 hr each day.

3. Nicotine that enters the blood is rapidly distributed to the
brain. As a result, effects of nicotine on the central nervous
system occur rapidly after a puff of cigarette smoke or after
absorption of nicotine from other routes of administration.
4. Acute and chronic tolerance develops to many effects of
nicotine. Such tolerance is consistent with reports that initial

13


use of tobacco products, such as in adolescents first beginning
to smoke. is usually accompanied by a number of unpleasant
symptoms which disappear following chronic tobacco use.

Chapter III: Nicotine: Sites and Mechanisms of Actions

1. Nicotine is a powerful pharmacologic agent that acts in the
brain and throughout the body. Actions include electrocortical
activation, skeletal muscle relaxation, and cardiovascular and
endocrine effects. The many biochemical and electrocortical
effects of nicotine may act in concert to reinforce tobacco use.
2. Nicotine acts on specific binding sites or receptors throughout
the nervous system. Nicotine readily crosses the blood-brain
barrier and accumulates in the brain shortly after it enters the
body. Once in the brain, it interacts with specific receptors and
alters brain energy metabolism in a pattern consistent with the
distribution of specific binding sites for the drug.

3. Nicotine and smoking exert effects on nearly all components of
the endocrine and neuroendocrine systems (including catechol-
amines, serotonin, corticosteroids, pituitary hormones). Some
of these endocrine effects are mediated by actions of nicotine
on  brain  neurotransmitter  systems (e.g., hypothalam-
ic-pituitary axis). In addition, nicotine has direct peripherally
mediated effects (e.g., on the adrenal medulla and the adrenal
cortex).

Chapter IV: Tobacco Use as Drug Dependence

1. Cigarettes and other forms of tobacco are addicting. Patterns of
tobacco use are regular and compulsive, and a withdrawal
syndrome usually accompanies tobacco abstinence.

2. Nicotine is the drug in tobacco that causes addiction. Specifi-
cally, nicotine is psychoactive ("mood altering") and can
provide pleasurable effects. Nicotine can serve as a reinforcer
to motivate tobacco-seeking and tobacco-using behavior. Toler-
ance develops to actions of nicotine such that repeated use
results in diminished effects and can be accompanied by
increased intake. Nicotine also causes physical dependence
characterized by a withdrawal syndrome that usually accompa-
nies nicotine abstinence.

3. The physical characteristics of nicotine delivery systems can
affect their toxicity and addictiveness. Therefore, new nicotine
delivery systems should be evaluated for their toxic and
addictive effects.

14


Chapter V: Tobacco Use Compared to Other Drug Dependen-
cies

1. The pharmacologic and behavioral processes that determine
tobacco addiction are similar to those that determine addiction
to drugs such as heroin and cocaine.
2. Environmental factors including drug-associated stimuli and
social pressure are important influences of initiation, patterns
of use, quitting, and relapse to use of opioids, alcohol, nicotine,
and other addicting drugs.

3. Many persons dependent upon opioids, alcohol, nicotine, or
other drugs are able to give up their drug use outside the
context of treatment programs; other persons, however, re-
quire the assistance of formal cessation programs to achieve
lasting drug abstinence.

4. Relapse to drug use often occurs among persons who have
achieved abstinence from opioids, alcohol, nicotine, or other
drugs.

5. Behavioral and pharmacologic intervention techniques with
demonstrated efficacy are available for the treatment of
addiction to opioids, alcohol, nicotine, and other drugs.

Chapter VI: Effects of Nicotine That May Promote Tobacco
Dependence

1. After smoking cigarettes or receiving nicotine, smokers per-
form better on some cognitive tasks (including sustained
attention and selective attention) than they do when deprived
of cigarettes or nicotine. However, smoking and nicotine do not
improve general learning.

2. Stress increases cigarette consumption among smokers. Fur-
ther, stress has been identified as a risk factor for initiation of
smoking in adolescence.

3. In general, cigarette smokers weigh less (approximately 7 lb
less on average) than nonsmokers. Many smokers who quit
smoking gain weight.

4. Food intake and probably metabolic factors are involved in the
inverse relationship between smoking and body weight. There
is evidence that nicotine plays an important role in the
relationship between smoking and body weight.

Chapter VII: Treatment of Tobacco Dependence

1. Tobacco dependence can be treated successfully.
2. Effective interventions include behavioral approaches alone
and behavioral approaches with adjunctive pharmacologic
treatment.

15


3. Behavioral interventions are most effective when they include
multiple components (procedures such as aversive smoking,
skills training, group support, and self-reward). Inclusion of too
many treatment procedures can lead to less successful out-
come.

4. Nicotine replacement can reduce tobacco withdrawal symp-
toms and may enhance the efficacy of behavioral treatment.

Appendix A: Trends in Tobacco Use in the United States

1. An estimated 32.7 percent of men and 28.3 percent of women
smoked cigarettes regularly in 1985. The overall prevalence of
smoking in the United States decreased from 36.7 percent in
1976 (52.4 million adults) to 30.4 percent in 1985 (51.1 million
adults).

2. In 1985, the mean reported number of cigarettes smoked per
day was 21.8 for male smokers and 18.1 for female smokers.
3. Smoking is more common in lower socioeconomic categories
(blue-collar workers or unemployed persons, less educated
persons, and lower income groups) than in higher socioeconom-
ic categories. For example, the prevalence of smoking in 1985
among persons without a high school diploma was 35.4 percent,
compared with 16.5 percent among persons with postgraduate
college education.

4. An estimated 18.7 percent of high school seniors reported daily
use of cigarettes in 1986. The prevalence of daily use of one or
more cigarettes among high school seniors declined between
1975 and 1986 by approximately 35 percent. Most of the decline
occurred between 1977 and 1981. Since 1976, the smoking
prevalence among females has consistently been slightly
higher than among males.

5. The use of cigars and pipes has declined 80 percent since 1964.
6. Smokeless tobacco use has increased substantially among
young men and has declined among older men since 1975. An
estimated 8.2 percent of 17- to 19-year-old men were users of
smokeless tobacco products in 1986.

Appendix B: Toxicity of Nicotine

1. At high exposure levels, nicotine is a potent and potentially
lethal poison. Human poisonings occur primarily as a result of
accidental ingestion or skin contact with nicotine-containing
insecticides or, in children, after ingestion of tobacco or tobacco
juices.

2. Mild nicotine intoxication occurs in first-time smokers, non-
smoking workers who harvest tobacco leaves, and people who

16


chew excessive amounts of nicotine polacrilex gum. Tolerance
to these effects develops rapidly.

3. Nicotine exposure in long-term tobacco users is substantial,
affecting many organ systems (Chapters II and III). Pharmace
logic actions of nicotine may contribute to the pathogenesis of
smoking-related diseases, although direct causation has not yet
been determined. Of particular concern are cardiovascular
disease, complications of hypertension, reproductive disorders,
cancer, and gastrointestinal disorders, including peptic ulcer
disease and gastroesophageal reflux.

4. The risks of short-term nicotine replacement therapy as an aid
to smoking cessation in healthy people are acceptable and
substantially outweighed by the risks of cigarette smoking.

17


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20


CHAPTER II

NICOTINE: PHARMACOKINETICS,
    METABOLISM, AND
   PHARMACODYNAMICS


CONTENTS

            ___
Introduction ........................................................... 25

                                        ~-~
Nicotine and Other Alkaloids in Various Tobacco Prod-
ucts ................................................................... 26

Pharmacokinetics and Metabolism of Nicotine ............ .29
  Absorption of Nicotine ..................................... .29
  Distribution of Nicotine in Body Tissues ............. ..3 1
  Elimination of Nicot.ine                    33
                         .......................................
    Pathways of Nicotine Metabolism ................  34
    Rate of Nicotine Metabolism ........................ .37
     Renal Excretion ....................................... .37
Nicotine and Cotinine Blood Levels During Tobacco
   Use .............................................................. 37
     Nicotine Levels ........................................... 37
     Cotinine Levels ........................................... 38
  Intake of Nicotine ............................................. 40
    Cigarette Smoking ...................................... .40
    Elimination Rate as a Determinant of Nicotine
     Intake by Cigarette Smoking .................... .40
    Biochemical Markers of Nicotine Intake ........ .41
Analytical Methods for Measuring Nicotine and
    Cotinine in Biological Fluids ............................ .42

Pharmacodynamics of Nicotine ................................. .43
  General Considerations ....................................... 43
Dose-Response .................................................. .44
  Tolerance ......................................................... 44

  Acute Sensitivity .............................................. .46
     Human Studies ........................................... 46
     Animal Studies ........................................... 46
    Mechanisms of Differences in Acute
     Sensitivity. .............................................. 47
  Tachyphylaxis (Acute Tolerance) ......................... .47
     Human Studies .......................................... .47
     Animal Studies ........................................... 49
    Mechanisms of Tachyphylaxis ...................... .49
  Chronic Tolerance ............................................. .50
     Human Studies. ......................................... .50

23


   Animal Studies ........................................... 51
  Mechanisms of Chronic Tolerance ................. .53
Pharmacodynamics of Nicotine and Cigarette Smok-
ing ............................................................... 55

Constituents of Tobacco Smoke Other Than Nicotine
With Potential Behavioral Effects .......................... .56
  Minor Tobacco Alkaloids .................................... .56
  "Tar" and Selected Constituents of Tobacco Smoke
   Which Contribute to Taste and Aroma .............. .58
  Carbon Monoxide ............................................... 59
Acetaldehyde and Other Smoke Constituents ......... .60

Summary and Conclusions ....................................... .60

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62

24


introduction

Chemicals with behavioral and physiological activity are delivered
to tobacco users when they smoke a cigarette or use other tobacco
products. Whether these chemicals are absorbed in quantities that
are of biological significance and whether such absorption is related
to the behavior of the tobacco user are critical issues in understand-
ing their role in addictive tobacco use. The scientific study of the
absorption processes, distribution within the body, and elimination
from the body of drugs and chemicals is called pharmacokinetics.
The study of drug and other chemical actions on the body, over time,
is called pharmacodynamics.

Pharmacokinetic and pharmacodynamic studies can be done
separately or together. An example of the latter is when a drug is
administered and its concentrations in the blood and its behavioral
and physiological actions are measured over time. Such studies can
reveal relationships among the dose of a drug, levels in the blood,
and effects on body functions.

The pharmacokinetics and pharmacodynamics of some tobacco
smoke constituents, particularly nicotine and carbon monoxide, have
been extensively studied. These studies show an orderly relationship
between the use of tobacco and the absorption of nicotine. Similarly,
the effects on behavioral and physiological functions, although
complex, are orderly and related to the pharmacokinetics of nicotine.
These data will be reviewed in this Section. Research shows that
nicotine is well absorbed from tobacco; that it is distributed rapidly
and in biologically active concentrations to body organs, including
the brain; and that nicotine is the major cause of the predominant
behavioral effects of tobacco and some of its physiologic conse-
quences.

One effect of nicotine, development of tolerance to its own actions,
is similar to that produced by other addicting drugs. Tolerance refers
to decreasing responsiveness to a drug or chemical such that larger
doses are required to produce the same magnitude of effect.
Tolerance to many actions of nicotine occurs in animals and humans.
Evidence for tolerance to nicotine and mechanisms of tolerance
development will be reviewed in this Chapter (see also Chapter VI).

Although nicotine has long been considered as the primary
pharmacologic reason for tobacco use, and the source of a number of
the physiological effects of tobacco, thousands of other chemicals are
present in tobacco. Most of these are delivered in such small
quantities that they appear to have little OF no behavioral conse-
quence. However, a few chemicals do appear to have behavioral
effects and there is a potential for numerous chemical interactions
that conceivably could have behavioral consequences. This Chapter
will conclude with an examination of tobacco smoke constituents

25


other than nicotine that rnay contribute to behavioral effects of
cigarette smoking.

The toxicity of nicotine is discussed in detail in Appendix B.

Nicotine and Other Alkaloids in Various Tobacco Products

Nicotine is a tertiary amine composed of a pyridine and a
pgrrolidine ring (Figure 1). Nicotine may exist in two different three-
dimensionally structured shapes,  called stereoisomers. Tobacco
contains only (S)-nicotine (also called l-nicotine), which is the most
pharmacoloqicaliy active form. Tobacco smoke also contains the less
potent (Rj-nicotine (also called d-nicotine) in quantities up to 10
percent of the total nicotine present (Pool, Godin, Crooks 1985).
Presumably some racemization occurs during the combustion pro-
cess.

The nicotine yield of cigarettes, as determined by standardized
smoking machine tests, is available for most brands. However, the
amount of nicotine in cigarettes or other tobacco products is not
specified by manufacturers. Because tobacco is a plant product, there
are differences in the amount of nicotine among and within different
types and strains of tobacco, including variations in different parts of
the plant, as well as differences related to growing conditions. Table
1 shows concentrations of nicotine and other alkaloids in several
different tobacco leaves used in making commercial tobacco prod-
ucts. Witliin a tobacco plant, leaves harvested from higher stalk
positions have higher concentrations of nicotine than from lower
stalk positions; ribs and stems of the leaves have the least (Rath-
kamp, Tso, Hoffmann 19731. Combining different varieties of tobacco
and different parts of the plant is a way to change the nicotine
concentration of commercial tobacco.

In a study of amounts of nicotine in the tobacco of 15 American
cigarette brands of differing machine-determined yields (Benowitz,
Hall et al. 19831, tobacco contained on average 1.5 percent nicotine
by weight. Nicotine yield of the cigarettes, as defined by Federal
Trade Commission smoking machine tests, was correlated inversely
with nicotine concentrations in the tobacco. Thus. tobacco of lower-
yield cigarettes tended to have higher concentrations of nicotine
than did tobacco of higher-yield cigarettes. However, lower-yield
cigarettes also contained less tobacco per cigarette, so the total
amount of nicotine contained per cigarette, averaging 8.4 mg, was
similar in different brands. Thus, low-yield cigarettes are low yield
not because of lower concentrations of nicotine in the tobacco, but
because they contain less tobacco and have characteristics which
remove tar and nicotine by filtration or dilution of smoke with air.
Concentrations of nicotine in commercial tobacco products are
summarized in Table 2.

26


NICOTINE

NORNICOTINE

N'-NITROSONORNICOTINE

NICOTINE N-OXIDE
(OXYNlCOTINEl

ANATAGINE        ANABASINE

N'-METHYLANATABINE   N`-METHYLANABASINE

NIMTYRINE       NORNICOTYRINE

COTININE       6'.OXOANABASINE

ANABASEINE

2.3'.DIPYPIDYL

METANICOTINE

PSEUDCOXYNICOTINE

FIGURE L-Chemical structures of nicotine and minor
        tobacco alkaloids
sOL'K(`E IRIP IY*:i

Although the major alkaloid in t.obacco is nicotine, there are other
alkaloids in tobacco which may be of pharmacologic importance.
These include nornicotine, anabasine, myosmine, nicotyrine, and
anatabine (Figure 1). These substances make up 8 to 12 percent of
the total alkaloid content of tobacco products (Table 1) (Piade and
Hoffmann 1980). In some varieties of tobacco, nornicotine concentra-
tions exceed those of nicotine (Schmeltz and Hoffmann 1977).

Typical quantities of the minor alkaloids in the smoke of one
cigarette are: nornicotine (27 to 88 pg), cotinine (9 to 50 pg),
anabasine (3 to 12 pgl, anatabine (4 to 14 pg). myosmine (9 pg), and
2,3' dipyridyl (7 to 27 pg). N'-methylanabasine, nicotyrine, nornicoty-
rine, and nicotine-N'-oxide have also been identified in cigarette
smoke (Schmeltz and Hoffmann 1977). Puffing characteristics,
especially puff frequency, influence the delivery of the component
alkaloids (Bush, Griinwald, Davis 1972).

27


TABLE l.-Alkaloid content of various tobaccos (mg/kg,
      dry basis)

Dar-k commercial tobacco

Anstabme              360       3x0       570       600

Anabasine

140       150        99       150

cotlnlne                195       140        90        40

M\oam,ne               45        50        60        30

2.3 -Dlpwld~l             1w       110        30        10

TABLE 2.-Nicotine content of various tobacco products

Nornicotine and anabasine have pharmacologic activity qualita-
tively similar to that of nicotine, with potencies of 20 to 75 percent
compared with that of nicotine, depending on the test system and the
animal (Clark, Rand, Vanov 1965). In addition to direct activity,
some of the minor alkaloids may influence the effects of nicotine. For
example, nicotyrine inhibits the metabolism of nicotine in animals
(Stalhandske and Slanina 1982).

The pharmacology of the minor tobacco alkaloids is discussed in
more detail in the last section of this Chapter.

28


Pharmacokinetics and Metabolism of Nicotine

Absorption of Nicotine

Nicotine is distilled from burning tobacco and is carried proximal-
ly on tar droplets (mass median diameter 0.3 to 0.5 urn) and probably
also in the vapor phase (Eudy et al. 19851, which are inhaled.
Absorption of nicotine across biological membranes depends on pH
(Armitage and Turner 1970; Schievelbein et al. 1973). Nicotine is a
weak base with a pKa (index of ionic dissociation) of 8.0 (aqueous
solution, 25oC). This means that at pH 8.0, 50 percent of nicotine is
ionized and 50 percent is nonionized. In its ionized state, such as in
acidic environments, nicotine does not rapidly cross membranes.

The pH of tobacco smoke is important in determining absorption
of nicotine from different sites within the body. The pH of individual
puffs of cigarettes made of flue-cured tobacco, the predominant
tobacco in most American cigarettes, is acidic and decreases progres-
sively with sequential puffs from pH 6.0 to 5.5 (Brunnemann and
Hoffmann 1974). At these pHs, the nicotine is almost completely
ionized. As a consequence, there is little buccal absorption of nicotine
from cigarette smoke, even when it is held in the mouth (Gori,
Benowitz, Lynch 1986). The smoke from air-cured tobaccos, the
predominant tobacco in pipes, cigars, and in a few European
cigarettes, is alkaline with progressive puffs increasing its pH from
6.5 to 7.5 or higher (Brunneman and Hoffmann 1974). At alkaline
pH, nicotine is largely nonionized and readily crosses membranes.
Nicotine from products delivering smoke of alkaline pH is well
absorbed through the mouth (Armitage et al. 1978; Russell, Raw,
Jarvis 1980).

When tobacco smoke reaches the small airways and alveoli of the
lung, the nicotine is rapidly absorbed. The rapid absorption of
nicotine from cigarette smoke through the lung occurs because of the
huge surface area of the alveoli and small airways and because of
dissolution of nicotine at physiological pH (approximately 7.4), which
facilitates transfer across cell membranes. Concentrations of nic-
otine in blood rise quickly during cigarette smoking and peak at its
completion (Figure 2). Armitage and coworkers (19751, measuring
exhalation of radiolabeled nicotine, found that four cigarette smok-
ers absorbed 82 to 92 percent of the nicotine in mainstream smoke,
another smoker presumed to be a noninhaler absorbed 29 percent,
and three nonsmokers (who were instructed to smoke as deeply as
possible) absorbed 30 to 66 percent.

Chewing tobacco, snuff, and nicotine polacrilex gum are of
alkaline pH as a result of tobacco selection and/or buffering with
additives by the manufacturer. The alkaline pH facilitates absorp-
tion of nicotine through mucous membranes. The rate of nicotine
absorption from smokeless tobacco depends on the product and the

29


M Cigarettes
A-----A Oral snuff
O--Q Chewing tobacco
F--O Nicotine gum
       N=lo

-10  0       30      60      90      120

            Minutes

FIGURE 2.-Blood nicotine concentrations during and after
      smoking cigarettes (1 l/3 cigarettes), using oral
      snuff (2.5 g), using chewing tobacco (average,
       7.9 g), and chewing nicotine gum (two 2-mg
       pieces)
`0, `I<(`?: Ht.ni.x!:,  ,`<?,rii,.r i'l :i, 1""

route of administration. With fine-ground nasal snuff, blood levels of
nicotine rise almost as fast as those observed after cigarette smoking

30


(Russell et al. 1981). The rate of nicotine absorption with the use of
oral snuff and chewing tobacco is more gradual. PVicotine is poorly
absorbed from the stomach due to the acidity of gastric fluid (Travel1
1960), but is well absorbed in the small intestine (Jenner, Gorrod,
Beckett 19731, which has a more alkaline pH and a large surface
area. Bioavailability of nicotine from the gastrointestinal tract (that
is, swallowed nicotine) is incomplete because of presystemic (first
pass) metabolism. whereby? after absorption into the portal venous
circulation, nicotine is metabolized by the liver before it reaches the
systemic venous circulation. This is in contrast to nicotine absorbed
through the lungs or oral,`nasal mucosa, which reaches the systemic
circulation without first passing through the liver. Nicotine base can
be absorbed through the skin, and there have been cases of poisoning
after skin contact with pesticides containing nicotine ~Faulkner
1933; Benowitz, Lake et al. 1987; Saxena and Scheman 1985).
Likewise, there is evidence of cutaneous absorption of and toxicity
from nicotine in tobacco field workers (Gehlbach et al. 19751.

Because of the complexity of cigarette smoking processes and use
of smokeless tobacco products, the dose of nicotine cannot be
predicted from the nicotine content of the tobacco or its absorption
characteristics. To determine the dose, one needs to measure blood
levels and know how fast the individual eliminates nicotine. This
topic, estimation of systemic doses of nicotine consumed from various
tobacco products, will be considered in a later section after discussion
of relevant pharmacokinetic issues.

Distribution of Nicotine in Body Tissues

After absorption into the blood, which is at pH 7.4, about 69
percent of the nicotine is ionized and 31 percent nonionized. Binding
to plasma proteins is less than 5 percent (Benowitz, Jacob et al.
1982). The drug is distributed extensively to body tissues with a
steady state volume of distribution averaging 180 liters (2.6 times
body weight (in kilograms)) (Table 3). This means that when nicotine
concentrations have fully equilibrated, the amount of nicotine in the
body tissues is 2.6 times the amount predicted by the product of
blood concentration and body weight. The pattern of tissue uptake
cannot be studied in humans, but it has been examined in tissues of
rabbits by measuring concentrations of nicotine in various tissues
after infusion of nicotine to steady state (Table 41. Spleen, liver,
lungs, and brain have high affinity for nicotine, whereas the affinity
of adipose tissue is relatively low.

After rapid intravenous (i.v.1 injection, concentrations of nicotine
decline rapidly because of tissue uptake of the drug. Shortly after i.v.
injection, concentrations in arterial blood. lung, and brain are high,
while concentrations in tissues such as muscle and adipose (major
storage tissues at steady state) are low. The consequence of this

31


TABLE 3.-Human pharmacokinetics of nicotine and
        cotinine

Nicotine           Cotinine

\`olumr of dknbutmn          180 L             88 L

1.300 mL/min


200 mL!min
(acid urinel

7`2 mL/min


12 mL/min

.sonrerx~l Clt31.3nCC           1,100 mlimin         60 mL/min

TABLE 4.-Steady state distribution of nicotine

Tissue to blood ratio

Blood

10

distribution pattern is that uptake into the brain is rapid, occurring
within 1 or 2 min, and blood levels fall because of peripheral tissue
uptake for 20 or 30 min after administration. Thereafter, blood
concentrations decline more slowly, as determined by rates of
elimination and rates of distribution out of storage tissues.

Rapid nicotine uptake into the brain has been demonstrated in
animal studies. Oldendorf (1974) showed a high degree of nicotine
uptake from blood in the first pass through the brains of rats.
Schmiterlow and colleagues (1967) showed by autoradiographic
techniques that high levels of nicotine were present in the brain 5
min after i.v. injections in mice and that most nicotine had been


cleared from the brain by 30 min. Stalhandske (1970) showed that
intravenously injected "C-nicotine is immediately taken up in the
brains of mice, reaching a maximum concentration within 1 min
after injection. Similar findings based on positron emission tomogra-
phy of the brain were seen after injection of "C-nicotine in monkeys
(Ma&re et al. 1976).

Nicotine inhaled in tobacco smoke enters the blood almost as
rapidly as after rapid i.v. injection except that the entry point into
the circulation is pulmonary rather than systemic venous. Because
of delivery into the lung, peak nicotine levels may be higher and lag
time between smoking and entry into the brain shorter than after
i.v. injection. After smoking, the action of nicotine on the brain is
expected to occur quickly. Rapid onset of effects after a puff is
believed to provide optimal reinforcement for the development of
drug dependence. The effect of nicotine deciines as it is distributed to
other tissues. The distribution half-life, which describes the move-
ment of nicotine from the blood and other rapidly perfused tissues,
such as the brain, to other body tissues, is about 9 min (Feyerabend
et al. 1985). Distribution kinetics, rather than elimination kinetics
(half-life, about 2 hr), determine the time course of central nervous
system (CNS) actions of nicotine after smoking a single cigarette.

Nicotine is secreted into saliva (Russell and Feyerabend 1978).
Passage of saliva containing nicotine into the stomach, combined
with the trapping of nicotine in the acidic gastric fluid and
reabsorption from the small bowel, provides a potential route for
enteric nicotine recirculation. This recirculation may account for
some of the oscillations in the terminal decline phase of nicotine
blood levels after iv. nicotine infusion or cessation of smoking
(Russell 1976).

Nicotine freely crosses the placenta and has been found in
amniotic fluid and the umbilical cord blood of neonates (Hibberd,
O'Connor, Gorrod 1978; Luck et al. 1982; Van Vunakis, Langone,
Milunsky 1974). Nicotine is found in breast milk and the breast fluid
of nonlactating women (Petrakis et al. 1978; Hill and Wynder 1979)
and in cervical mucous secretions (Sasson et al. 1985). Nicotine is
also found in the freshly shampooed hair of smokers and of
nonsmokers environmentally exposed to tobacco smoke (Haley and
Hoffmann 1985).

Elimination of Nicotine

Nicot.ine is extensively metabolized, primarily in the liver, but also
to a small extent in the lung (Turner et al. 1975). Renal excretion of
unchanged nicotine depends on urinary pH and urine flow, and may
range from 2 to 35 percent, but typically accounts for 5 to 10 percent
of total elimination (Benowitz, Kuyt et al. 1983; Rosenberg et al.
1980).

33


fi --p- Q%j
  NICOTINE     L 5'4iYDROXYNICOTINE       NICOTINE IMINIUM
1 \,                       ION

FLAVOPROTEIN

ALDEHYDE
OXIDASE

URINARY
EXCRETION

FIGURE 3.-Major pathways of nicotine metabolism

Pathlcays of ,Vicotine Metabolism

The primary metabolites of nicotine are cotinine and nicotine-N'-
oxide (Figure 3). Cotinine is formed in the liver in a two-step process,
the first of which involves oxidation of position 5 of the pyrrolidine
ring in a cytochrome P-450-mediated process to nicotine-A' l5 I-imini-
urn ion (Peterson, Trevor, Castagnoli 19871. In the second step the
iminium ion is metabolized by a cytoplasmic aldehyde oxidase to
cotinine (Hibberd and Gorrod 1983).

Cotinine itself is also extensively metabolized, with only about 17
percent excreted unchanged in the urine (Benowitz. Kuyt et al.
1983). Several metabolites of cotinine have been reported, including
trans-3'-hydroxycotinine (McKennis, Turnbull et al. 19631, 5'-hydrox-
ycotinine (Bowman and McKennis 19621, cotinine-N-oxide (Shulgin
et al. 19871, and cotinine methonium ion (McKennis, Turnbull,
Bowman 1963) (see Figure 4). Little is known about the quantitative
importance of these metabolites. Trans-3'-hydroxycotinine appears
to be a major metabolite (Jacob, Benowitz, Shulgin 1988; Neurath et
al. 1987), with urinary concentrations exceeding cotinine concentra-
tions by twofold to threefold. Cotinine N-oxide is a minor metabolite
in humans, accounting for approximately 3 percent of ingested
nicotine (Shulgin et al. 1987). Subsequent oxidative degradation of
the pyrrolidine ring gives rise to 3-pyridylacetic acid. This compound
has been identified in human urine (McKennis, Schwartz, Bowman
1964), but no quantitative data are available.

34


NICOTINE

COTNNE

TRANS - J' HYDROXYCOTININE       COTININE-N-OXIDE

NICOTINE-N-OXIDE

NORNICOTINE

5'. HYDROXYCOTININE      r. 13. PYR,DYL, -`d-0X0-to-METHYLBUTYRAMIDE

NICOTINE ISOMETHONIUM ION

CCTININE METHONIUM ION

FIGURE 4.-Structures of nicotine and its major
       metabolites

SOURCE P Jacob 111 tw,th perm,simnl

35


Nicotine-l'-N-oxide is quantitatively a minor metabolite of nic-
otine. Oxidation of the nitrogen atom of the pyrrolidine ring depends
on a microsomal flavoprotein syst.em and produces a mixture of the
two diasterisomers, l'-(R)-2'-(S)-&- and l'-(S)-2'-(S)-trurts-nicotine-l'-
N/-oxide (Booth and Boyland 1970). After i.v. injection, 100 percent of
nicotine-N'-oxide is excreted unchanged in the urine, indicating no
further metabolism (Beckett, Gorrod, Jenner 1971a). However, after
oral administration only 30 percent is recovered in the urine as
nicotine-N'-oxide; the remainder is recovered as nicotine and its
metabolites. To evaluate the possibility of reduction of nicotine-N'-
oxide in the gastrointestinal tract, rectal administration of nicotine-
N'-oxide was performed for experimental purposes. Less than 10
percent was recovered in the urine as nicotine-N'-oxide (Beckett,
Gorrod, Jenner 1970). These findings indicate reduction of nicotine-
N'-oxide back to nicotine within the human gastrointestinal tract,
believed to be a consequence of bacterial action.

Experiments in rats indicate that significant amounts of nicotine-
N'-oxide are converted to nicotine both in vitro and in vivo (Dajani,
Gorrod, Beckett 1975a,b). Nicotine and cotinine have been measured
in the blood of rats administered nicotine-N,N'-dioxide and nicotine-
N'-oxide in drinking water (Sepkovic et al. 1984, 1986). Thus, while
reduction of nicotine-N'-oxide to nicotine appears to be bacterial in
humans, it may be mediated by endogenous enzymes in other
species.

Quantitative aspects of the conversion of nicotine to its metabo-
lites have not been well defined. Studies of cotinine excretion in
urine collected for 24 hr after i.v. nicotine injection indicate less than
10 percent of nicotine is excreted as cotinine in nonsmokers
compared with an average of 25 percent in smokers (Beckett, Gorrod,
Jenner 1971b). Another study, comparing 24-hr urinary excretion of
cotinine with nicotine content of cigarette butts after smoking,
indicated 46 percent recovery as cotinine (Schievelbein 1982).
However, both of these studies underestimate the conversion of
nicotine to cotinine because the urine collection period was too short.
In cigarette smokers, cotinine has a half-life averaging 18 to 20 hr
(Benowitz, Kuyt et al. 1983), so that in 24 hr only a little more than
half of cotinine is recovered. Urine collection for at least 72 hr is
necessary to recover more than 90 percent of cotinine in most
subjects. In addition, since only 17 percent of cotinine is excreted
unchanged (Benowitz, Kuyt et al. 1983), urinary recovery analysis
underestimates the cotinine generation rate.

At steady stat.e, the rate of metabolite excretion reflects the rate at
which the metabolites are generated. After i.v. dosing, 100 percent of
nicotine-N'-oxide but only 17 percent of cotinine are excreted
unchanged in the urine. Based on a ratio of urinary cotinine to
nicotine-N'-oxide of 2.9 and based on excretion of that 17 percent of

36


cotinine and 100 percent of nicotine-N'-oxide unchanged in the
urine, the relative generation rate of cotinine compared with that of
nicotine-N'-oxide is calculated to be 17 to 1 (Benowitz 1986b).
Because 4 percent of nicotine is excreted as nicotine-N'-oxide (Jacob
et al. 1986; Beckett, Gorrod, Jenner 1971a), about 70 percent of
nicotine appears to be converted to cotinine. Quantitative data on
other metabolites that may have pharmacologic activity, such as
nicotine isomethonium ion and nornicotine, are not available.

Rate of Nicotine Metabolism

The rate of nicotine metabolism can be determined by measuring
blood levels after administration of a known nicotine dose. In one
study, cigarette smokers were given iv. infusions of nicotine for 30 to
60 min, and total and renal clearances were computed (Benowitz,
Jacob et al. 1982). Total clearance ia term which describes the
capacity to eliminate a drug) averaged 1,300 ml/mix-i. Nonrenal
clearance averaged 1,100 mL/min (Table 31, which represents about
70 percent of liver blood flow. Because nicotine is metabolized
mainly by the liver (data in animals indicate only a small degree of
metabolism by the lung) (Turner, Sillett, McNicol 19771, this means
that about 70 percent of the drug is extracted from the blood in each
pass through the liver. On the average, 85 or 90 percent of nicotine is
metabolized by the liver.

Renal Excretion

Nicotine is excreted by glomerular filtration and tubular secretion
within the kidney. Depending on urinary pH and urine flow rate,
variable amounts of nicotine are reabsorbed by the kidney tubules.
In acidic urine, where nicotine is mostly ionized and tubular
reabsorption is minimized, renal clearance of nicotine may be as
high as 600 mL/min (urinary pH 4.4) (Benowitz, Kuyt et al. 1983;
Rosenberg et al. 1980). In alkaline urine, a larger fraction of nicotine
is not ionized. Tubular reabsorption of nonionized nicotine results in
lower rate of excretion and reduced renal clearances as low as 17
mL/min (urine pH 7.0). When urine pH is uncontrolled, averaging
5.8, renal clearance averages about 100 mL/min, accounting for the
elimination of 10 to 15 percent of the daily nicotine intake.

Nicotine and Cotinine Blood Levels During Tobacco Use
Nicotine Levels

Plasma nicotine concentrations (or concentrations in blood, which
are similar) sampled in the afternoon in smokers generally range
from 10 to 50 ng/mL. The increment in blood nicotine concentration
after smoking a single cigarette ranges from 5 to 30 ng/mL,
depending on how the cigarette is smoked (Armitage et al. 1975;

37


Herning et al. 1983; Isaac and Rand 1972). Peak blood levels of
nicotine are snnilar, although the rate of nicotine increase is slower
for cigar smokers and snuff and chewing tobacco users compared
with that for cigarette smokers (Armitage et al. 1978; Turner, Sillett,
McNicol 1977: Gritz et al. 1981; Russell, Raw, Jarvis 1980; Russell et
al. 1981) (Figure 2). Pipe smokers, particularly those who have
previously smoked cigarettes and who inhale, may have blood and
urine levels of nicotine as high as those of cigarette smokers
(McCusker, McNabb, Bone 1982; Turner, Sillett, McNicol 1977; Wald
et al. 1984).

The earliest published studies of nicotine elimination kinetics
reported half-lives of 20 to 40 min (Armitage et al. 1975; Isaac and
Rand 1972). In those studies, drug blood levels were followed only for
30 to 60 min, which is not long enough to determine the elimination
half-life. Thus, half-lives were based on blood levels which included
the distribution phase. When blood levels are followed for several
hours after the end of nicotine infusion, a log-linear decline of blood
levels with a half-life of about 2 hr is observed (Benowitz, Jacob et al.
1982; Feyerabend, Ings, Russell 1985).

The half-life of a drug is useful in predicting its accumulation rate
in the body with repetitive doses and the time course of its decline
after cessation of dosing. Assuming a half-life of 2 hr, one would
predict nicotine to accumulate over 6 to 8 hr (3 to 4 half-lives) of
regular smoking and persist at significant nicotine levels for 6 to 8 hr
after cessation of smoking. If a smoker smokes until bedtime,
significant nicotine levels should persist all night. Studies of blood
levels in regular cigarette smokers confirm these predictions (Figure
5) (Russell and Feyerabend 1978; Benowitz, Kuyt, Jacob 1982). Peaks
and troughs follow the use of each cigarette, but as the day
progresses, trough levels rise and the influence of peak levels
becomes less important. Thus, nicotine is not a drug to which people
are exposed intermittently and that is eliminated rapidly from the
body. To the contrary, smoking represents a multiple dosing
situation with considerable accumulation during smoking and with
persistent levels for 24 hr of each day.

Cotinine Leljels

Cotinine levels are of particular interest as qualitative markers of
tobacco use and quantitative indicators of nicotine intake. Cotinine
is present in the blood of smokers in much higher concentrations
than nicotine. Cotinine blood levels average about 250 to 300 ng/mL
in groups of cigarette smokers (Benowitz, Hall et al. 1983; Haley,
Axelrad, Tilton 1983; Langone, Van Vunakis, Hill 1975; Zeidenberg
et al. 1977). After stopping smoking, levels decline with a half-life
averaging 18 to 20 hr (range 11 to 37 hr). But because of the long
half-life, there is much less fluctuation in cotinine concentrations

38


  7         --o-- Usual brand
        T
-      T          -A-  Low nicotine
           High nicotine

N = 10

l2 r

N=7

2-l      I      I      I      I            I
0800 ,200 16.X 2016 24'" 0~20 oa3C

             Clock time

FIGURE S-Blood nicotine and carboxyhemoglobin
      concentrations in subjects smoking high
      nicotine (`2.5 mg) and low nicotine (0.4 mg)
      Kentucky reference cigarettes and their usual
      brand (average nicotine yield, 1.2 mg) of
       cigarettes
VOTE Sub,rcts .n,flhrd rin LI i,\id si.hddr n, , ~,c..w,,e I)\, ,> /h`,,' !,.`A' /PI, 1 . :11,1 1, 10 I, SW ,I 11, ,111 :! 1$11,,1
o, 13, c,~z,w,~P, da>. blood ..1,11~1~?, nrrr <1?llrrlK ,.1-l !W11111~ !I ? 11?\1 .l.!>l~l:ilA x IL,i'i'!`.'
SOL'K(`E Rrnm\,t/ ir;~i( .l,ic ,h l'lhl

39


throughout the day than in nicotine concentrations. As expected,
there is a gradual increase in cotinine levels during the day, peaking
at the end of smoking and persisting in high concentrations
overnight.

Intake of Nicotine

Cigarette Smoking

Nicotine intake from single cigarettes has been measured by
spiking cigarettes with "C-labeled nicotine (Armitage et al. 1975).
That study of eight subjects, each smoking a single filter-tipped
cigarette, indicated an intake range of 0.36 to 2.62 mg. Intake was
higher in smokers than in nonsmokers. Intake of nicotine from
smoking a single cigarette or with daily cigarette smoking has been
estimated by methods similar to those used in drug bioavailability
studies (Benowitz and Jacob 1984; Feyerabend, Ings, Russell 1985).
Metabolic clearance of nicotine was determined after i.v. injection.
Metabolic clearance data were then used in conjunction with blood
and urinary concentrations of nicotine measured during a period of
smoking to determine the intake of nicotine. In five subjects, average
intake of nicotine per cigarette was 1.06 mg (range, 0.58 to 1.49 mg)
(Feyerabend, Ings, Russell 19851. In 22 cigarette smokers, 13 men
and 9 women who smoked an average of 36 cigarettes/day (range 20
to 621, the average daily intake was 37.6 mg, with a range from 10.5
to 78.6 mg (Benowitz and Jacob 1984). Nicotine intake per cigarette
averaged 1.0 mg (range 0.37 to 1.56 mg). Intake per cigarette did not
correlate with yields obtained by smoking machine using standard
Federal Trade Commission methods. This is because smoking
machines smoke cigarettes in a uniform way, using a fixed puff
volume (35 mL1, flow rate (over 2 secl, and interval (every minute).
Smokers smoke cigarettes differently, changing their puffing behav-
ior to obtain the desired amount of tobacco smoke and nicotine.

Elimination Rate as a Determinant of Nicotine Intake by
Cigarette Smoking

There is considerable evidence that smokers adjust their smoking
behavior to try to regulate or maintain a particular level of nicotine
in the body (Gritz 1980; Russell 1976). For example, when the
availability of cigarettes is restricted, habitual smokers can increase
intake of nicotine per cigarette 300 percent compared with the
intake of unrestrict,ed smoking (Benowitz, Jacob, Koslowski et al.
1986).
Techniques for measuring daily intake of nicotine (Benowitz and
Jacob 1984) have been applied to study the influence of elimination
on nicotine intake. The rate of renal elimination of nicotine was
manipulated by administration of ammonium chloride or sodium

40


bicarbonate to acidify or alkalinize the urine: respectively (Benowitz
and Jacob 1985). Compared with daily excretion during placebo
treatment (3.9 mg nicotine/day), acid loading increased (to 12
mglday) and alkaline loading decreased (to 0.9 mglday) daily
excretion of nicotine. The total intake of nicotine averaged 38
mg/day. Average blood nicotine concentrations were similar in
placebo and bicarbonate treatment conditions but were 15 percent
lower during ammonium chloride treatment. Daily intake of nicotine
was 18 percent higher during acid loading, indicating compensation
for increased urinary loss. The compensatory increase in nicotine
consumption was only partial, replacing about half of the excess
urinary nicotine loss. Bicarbonate treatment had no effect on
nicotine consumption, consistent with the small magnitude of effect
on excretions of nicotine in comparison to total daily intake.

These results seem compatible with the suggestion of Schachter
(1978) that emotional stress, which results in more acidic urine,
might accelerate nicotine elimination from the body and thereby
increase cigarette smoking. But caution must be exercised in
applying these findings to usual smoking situations. These studies
were performed under conditions of extreme urinary acidification or
alkalinization, so that the changes in renal clearance would be
maximized, Even with extreme differences in urinary pH, differ-
ences in overall nicotine elimination rate and smoking behavior
were modest. This is because renal excretion is a minor pathway for
elimination of nicotine; most is metabolized. Smaller changes in
urinary pH, such as occur spontaneously throughout the day or that
might be related to stressful events, would not be expected to
substantially influence nicotine elimination or smoking behavior.

Biochemical Markers of Nicotine Intake

Absorption of nicotine from tobacco smoke provides a means of
verification and quantitation of tobacco consumption. The general
strategy is to measure concentrations of nicotine, its metabolites
(such as cotinine), or other chemicals associated with tobacco smoke
in biological fluids such as blood, urine, or saliva. Different measures
vary in sensitivity, specificity, and difficulty of analysis. Different
investigators have used blood or urinary nicotine concentrations,
blood or salivary or urinary cotinine concentrations, expired carbon
monoxide or carboxyhemoglobin concentrations, or plasma or sali-
vary thiocyanate (a metabolite of hydrogen cyanide, a vapor phase
constituent) concentrations as measures of tobacco smoke consump-
tion.

Relationships among daily intake of nicotine, daily exposure to
nicotine (that is, blood concentrations of nicotine integrated over 24
hr), various parameters of cigarette consumption, and different
measures of nicotine intake have been examined experimentally

41


during ad libitum cigarette smoking on a research ward (Benowitz
and Jacob 1984). The best biochemical correlate to nicotine intake
and exposure in this study was a random blood nicotine concentra-
tion measured at 4 p.m. This level did not depend on when the last
cigarette was smoked. This finding is consistent with the observation
that nicotine levels accumulate throughout the day and plateau in
the early afternoon (see Figure 5). At steady state, with regular
smoking throughout the day, there should be a reasonably good
correlation between nicotine concentrations and daily intake. Car-
boxyhemoglobin (COHb) concentrations in the afternoon were the
next best markers of nicotine intake. Also, morning (8 a.m.) levels of
nicotine and COHb correlated with intake, presumably reflecting
persistence of nicotine and COHb in the blood from exposure on the
previous day.

Although cotinine is a highly specific marker for nicotine expo-
sure, blood levels of cotinine across subjects in this study did not
correlate as closely with nicotine intake as did blood levels of
nicotine or COHb (Benowitz and Jacob 1984). This is probably due to
individual variability in fractional conversion of nicotine to cotinine
and in the elimination rate of cotinine itself.

Because of its relatively long half-life, cotinine levels are less
sensitive than nicotine levels to smoking pattern, that is, when the
last cigarette was smoked. For longitudinal within-subject studies,
the cotinine level would be expected to be a good marker of changes
in nicotine intake. Cotinine measurements have become the most
widely accepted method for assessing the intake of nicotine in long-
term studies of tobacco use (see also Chapter V).

As expected by the known variation in renal clearance due to
effects of urinary flow and pH, urinary concentrations of nicotine did
not correlate well with nicotine intake (Benowitz and Jacob 1984). In
contrast, urinary cotinine, which is less influenced by urinary flow
or pH, was as good a marker as blood cotinine concentration.
Salivary and urinary cotinine concentrations correlate well (r = 0.8
to 0.9) with blood cotinine concentrations (Haley, Axelrad, Tilton
1983; Jarvis et al. 1984). Therefore, salivary or urine cotinine
concentrations should be almost as useful as blood levels in
indicating nicotine intake.

Analytical Methods for Measuring Nicotine and Cotinine in
Biological Fluids

Determination of nicotine concentrations in biological fluids
requires a sensitive and specific method, because concentrations of
nicotine in smokers' blood are generally in the low nanogram per
milliliter range and a number of metabolites are also present.
Cotinine concentrations in blood are generally about tenfold greater
than nicotine concentrations, and as a result, less sensitive analyti-

42


cal methodology may be acceptable. Methods with adequate sensitiv-
ity for determination of nicotine and cotinine in smokers' blood
include gas chromatography (GC) (Curvall, Kazemi-Vala, Enzell
1982; Davis 1986; Feyerabend, Levitt, Russell 1975; Hengen and
Hengen 1978; Jacob, Wilson, Benowitz 1981; Vereby, DePace, Mule
1982), radioimmunoassay (RIA) (Langone, Gjika, Van Vunakis 1973;
Castro et al. 1979; Knight et al. 1985), enzyme-linked immunosorbent
assay (ELISA) (Bjercke et al. 1986), high performance liquid chroma-
tography (HPLC! (Machacek and Jiang 1986; Chien, Diana, Crooks,
in press), and combined gas chromatograph-mass spectrometry (GC-
MS) (Dow and Hall 1978; Gruenke et al. 1979; Jones et al. 1982;
Daenens et al. 1985). For reasons of sensitivity, specificity, and
economy, GC and RIA are the most frequently used methods. GC-MS
is a highly sensitive and specific technique, but the expense has
discouraged its routine use. HPLC is less sensitive than GC for
nicotine and cotinine determination. Although recently reported
methods (Machacek and Jiang 1986; Chien, Diana, Crooks, in press)
appear to have adequate sensitivity for determining concentrations
in plasma, relatively large sample volumes are required. Concentra-
tions of nicotine and cotinine in urine are tenfold to hundredfold
greater than concentrations in plasma or saliva (Jarvis et al. 1984),
and a variety of chromatographic and immunoassay techniques meet
sensitivity requirements.

The choice of a particular method depends on the biological fluid
to be assayed; the need for sensitivity, precision, and accuracy; and
economic considerations. Chromatographic methods, particularly
those utilizing high-resolution capillary columns and specific detec-
tors such as nitrogen-phosphorus detectors or a mass spectrometer,
provide the greatest specificity. On the other hand, immunoassay
techniques are operationally simpler, generally require smaller
samples, and may be less expensive than chromatographic methods.
A drawback to immunoassay methods is the potential for cross-
reactivity of the antibody with metabolites or endogenous sub-
stances. There is generally a good correlation between results
obtained by GC and RIA for plasma cotinine concentrations (r = 0.94)
(Gritz et al. 1981; Biber et al. 1987). In an interlaboratory comparison
study (Biber et al. 19871, cotinine concentrations in smokers' urine
measured by RIA were generally higher than concentrations deter-
mined by GC, whereas in nonsmokers' urine spiked with cotinine
RIA and GC values were similar. These results suggest that nicotine
metabolites cross-react with the antibody against cotinine, at least in
some of the RIA methods.

Pharmacodynamics of Nicotine
General Considerations

This Section will focus on the relationship between nicotine levels
in the body and their effects on behavior and physiological function

43


(pharmacodynamics). These data show how pharmacodynamic fac-
tors determine some of the consequences of cigarette smoking, Two
issues are particularly relevant in understanding the pharmacody-
namics of nicotine: a complex dose-response relationship and the
level of tolerance that is either preexisting or is produced by
administration of nicotine.

Dose-Response

The relationship between the dose of nicotine and the resulting
response (dose-response relationship) is complex and varies with the
specific response that is measured. In pharmacology textbooks,
nicotine is commonly mentioned as an example of a drug which in
low doses causes ganglionic stimulation and in high doses causes
ganglionic blockade following brief stimulation (Comroe 1960). This
type of effect pattern is referred to as "biphasic." Dose-response
characteristics in functioning organisms (in vivo) are often biphasic
as well, although the mechanisms are far more complex. For
example, at very low doses, similar to those seen during cigarette
smoking, cardiovascular effects appear to be mediated by the CNS,
either through activation of chemoreceptor afferent pathways or by
direct effects on the brain stem (Comroe 1960; Su 1982). The net
result is sympathetic neural discharge with an increase in blood
pressure and heart rate. At higher doses, nicotine may act directly
on the peripheral nervous system, producing ganglionic stimulation
and the release of adrenal catecholamines. With high doses or rapid
administration, nicotine produces hypotension and slowing of heart
rate, mediated either by peripheral vagal activation or by direct
central depressor effects (Ingenito, Barrett, Procita 1972; Porsius
and Van Zwieten 1978; Henningfield, Miyasato, Jasinski 1985).

Tolerance

A second pharmacologic issue of importance is development of
tolerance; that is, after repeated doses, a given dose of a drug
produces less effect or increasing doses are required to achieve a
specified intensity of response. Functional or pharmacodynamic
tolerance can be further defined as where a particular drug
concentration at a receptor site (in humans approximated by the
concentration in blood) produces less effect than it did after a prior
exposure. Dispositional or pharmacokinetic tolerance refers to
accelerated drug elimination as a mechanism for diminished effect
after repeated doses of a drug. Behavioral tolerance refers to
compensatory behaviors that reduce the impact of a drug to
adversely affect performance. Such tolerance can occur following
intermittent exposures to a drug such that there is minimal
development of functional or dispositional tolerance.

44


Most studies of drug tolerance have focused on tolerance which
develops as a drug is chronically administered. If the tolerance
develops within one or two doses, it is referred to as acute tolerance
or tachyphylaxis. If tolerance develops after more prolonged use, the
tolerance is referred to as acquired or chronic tolerance. Individual
differences in sensitivity to the first dose of a drug also frequently
exist. Those individuals who exhibit a reduced response to a specified
drug dose or require a greater dose to elicit a specified level of
response are said to be tolerant to the drug. This form of tolerance is
referred to as first-dose tolerance, drug sensitivity, or innate drug
responsiveness. For sake of clarity, this Report will reserve the term
tolerance to describe reduction in the response to nicotine during the
course of or following a previous exposure and will use acute drug
sensitivity to describe responsiveness to an initial dose.

Studies of tolerance to nicotine began in the late 19th century. In a
series of studies of fundamental importance to the understanding of
the nervous system, as well as to understanding the pharmacology of
nicotine, Langley (1905) and Dixon and Lee (1912) studied the effects
of repeated nicotine administration on a variety of animal species
and on in vitro tissue preparations. Several findings emerged which
have been widely verified and extended to other species and
responses. These include: (1) With repeated dosing, responses dimin-
ished to nearly negligible levels; (2) After tolerance occurred,
responsiveness could be restored by increasing the size of the dose; (3)
After a few hours without nicotine, responsiveness was partially or
fully restored.

After smoking a cigarette, people who have not smoked before
("naive smokers") usually experience a number of effects that
become generally uncommon among experienced smokers. For
example, retrospective reports by smokers indicate that initial
exposure to tobacco smoke produced dizziness, nausea, vomiting,
headaches, and dysphoria, effects that disappear with continued
smoking and are rarely reported by chronic smokers (Russell 1976;
Gritz 1980). Tolerance may also develop to toxic effects, such as
nausea, vomiting, and pallor, during the course of nicotine poisoning,
despite persistence of nicotine in the blood in extremely high
concentrations (200 to 300 ng/mL! (Benowitz, Lake et al. 1987).

A systematic analysis of the various forms of tobacco smoke
tolerance has not been carried out. There are a few studies
comparing the effects elicited by an acute exposure to tobacco in
nonsmokers and smokers. Clark and Rand (1968) studied the effect of
smoking cigarettes of varying nicotine content on the knee-jerk
reflex and reported that high-nicotine cigarettes suppressed this
reflex to a greater degree than did low-nicotine cigarettes. This effect
was more pronounced at each nicotine dose in nonsmokers and light
smokers compared to heavy smokers. These findings suggested that

45


tolerance is due to altered sensitivity to nicotine. Tolerance to
nicotine is not complete because even the heaviest smokers experi-
ence symptoms such as dizziness, nausea, and dysphoria when they
suddenly increase their smoking rates (Danaher 1977). Evidence
indicates that the majority of the psychological actions of tobacco
smoke result from nicotine (Russell 1976; Chapter VII). Thus, most of
the tolerance to effects of tobacco smoke that occurs following
chronic tobacco use is due to the development of tolerance to
nicotine.

Acute Sensitivity
Human Studies

Studies which have indicated that individuals differ in response to
tobacco smoke or nicotine have used smokers as the experimental
subjects. Consequently, whether individual differences are due to
differences in acute sensitivity to nicotine that have persisted during
chronic tobacco use or are due to differences in the development of
tolerance is unknown.

Nesbitt (1973) and Jones (1986) noted that individual smokers
differ with respect to the effects of smoking a standard cigarette on
heart rate, but it is not clear from these studies whether these
differences in responsiveness are due to differences in sensitivity to
nicotine or to differences in the dose and kinetics of nicotine.
Benowitz and colleagues (1982) observed individual differences in the
effects of iv. injections of nicotine on heart rate, blood pressure, and
fingertip skin temperature. Differences were not explained by
differences in blood levels, indicating differential sensitivity to
nicotine.

Animal Studies

Studies using laboratory animals indicate that differences in acute
sensitivity to nicotine exist. Inbred rat and mouse strains differ in
sensitivity to the effects of nicotine on locomotor activity (Garg 1969;
Battig et al. 1976; Schlatter and Battig 1979; Hatchell and Collins
1980; Marks, Burch, Collins 1983b). Mouse strains also differ in the
direction of the effect (increased or decreased activity). The mouse
strains that differ in sensitivity to the effects of injected nicotine on
locomotor activity also differ in the magnitude of response to a
standard dose of tobacco smoke (Baer, McClearn, Wilson 1980).
Inbred mouse strains also differ in sensitivity to the effects of
nicotine on body temperature, heart rate, and acoustic startle
response (Marks, Burch, Collins 1983a; Marks et al. 1985, 1986), as
well as in sensitivity to nicotine-induced seizures (Tepper, Wilson,
Schlesinger 1979; Miner, Marks, Collins 1984, 1986). These findings
indicate that genetic factors may influence the sensitivity of rats and

46


mice to the first dose of nicotine. The importance of genetically
determined differences in human sensitivity to the effects of nicotine
administered in tobacco smoke remains to be determined.

Mechanisms of Differences in Acute Sensiticit?

Differences between inbred mouse and rat strains in sensitivity to
the effects elicited by a single injected dose of nicotine do not appear
to result from differences in rate of nicotine metabolism (Petersen,
Norris, Thompson 1984) or from differences in brain nicotine
concentration following intraperitoneal injection !Hatchell and
Collins 1980; Rosecrans 1972; Rosecrans and Schechter 1972). Thus,
rat and mouse strains differ in tissue sensitivity to the effects of
nicotine. Differences among mouse strains in sensitivity to nicotine
do not appear to be due to differences in the number or affinity of
brain nicotine receptors that are measured via the binding of 3H-
nicotine (Marks, Burch, Collins, 1983b). Mouse stocks that are more
sensitive to nicotine-induced seizures do have greater numbers of
hippocampal nicotine receptors that bind "`1-bungarotoxin (BTX)
(Miner, Marks, Collins 1984, 1986). Some of the differences in
sensitivity to nicotine between genetically defined stocks of animals
may be related to differences in the number of nicotine receptors in
specific regions of the brain.

Tachyphylaxis (Acute Tolerance)
Human Studies

Systematic studies of tachyphylaxis or acute tolerance to effects of
tobacco in nonsmokers have not been reported. There is evidence
that tachyphylaxis does develop to effects of tobacco and nicotine in
humans. Smokers frequently report that the first cigarette of the day
is the best and that subsequent cigarettes are "tasteless" (Russell
1976; Henning-field 1984). Smoking a single standard cigarette after
24 hr of abstinence increases heart rate, whereas smoking an
identical cigarette during the course of a normal day fails to change
heart rate (West and Russell 19871. Fewer standard puffs were
required to produce nausea at the beginning of the day (following 8
to 10 hr of tobacco abstinence) or from high-nicotine cigarettes than
at the end of the day or from low-nicotine cigarettes (Henningfield
1984). Complete tolerance to nausea and vomiting developed over 8
hr in a woman in the course of an accidental nicotine poisoning,
despite persistently toxic blood levels of nicotine (Benowitz, Lake et
al. 1987). These findings suggest that tolerance which is lost and
regained during short periods of abstinence from tobacco is tolerance
to nicotine.

Tolerance develops very rapidly to several effects of nicotine.
Rosenberg and colleagues (1980) studied the effects of i.v. nicotine

47


injections on arousal level, heart rate, and blood pressure. In these
experiments, six healthy smokers, 21 to 35 years of age, received six
series of nicotine injections spaced 30 min apart. Each series of
injections consisted of 10 2+g/kg injections spaced 1 min apart.
Subjects reported a pleasant sensation after the first series of
injections, but this response was not observed thereafter. Heart rate
and blood pressure values remained above baseline, but there was
little increment with successive injections, despite nicotine blood
level increases which were similar to those observed after the first
series of injections, In contrast, skin temperature fell progressively
during the period of nicotine dosing, gradually returning to baseline
at the end of the study. These data indicated rapid development of
tolerance to subjective effects and heart rate and blood pressure
responses, but tolerance was not complete because heart rate and
blood pressure remained above baseline. Henningfield (1984) also
assessed subjective responses of human subjects after i.v. injections
with nicotine at lo-min intervals. The subjective response of "liking"
the effects of nicotine was lost after five or six injections. Benowitz
and coworkers (1982) studied the effect of a 30-min infusion of
nicotine at a rate of 1 to 2 ug/kg/min. Shortly after initiation of
infusion, heart rate and blood pressure increased, but the increase
did not continue even though plasma nicotine concentrations
continued to rise during the continuous infusion. Maximal cardiovas-
cular changes were seen within 5 to 10 min, whereas maximal
plasma nicotine levels were not reached until 30 min. These findings
indicate that tachyphylaxis to the effects of nicotine may develop in
humans within 5 to 10 min, the time required to smoke one cigarette.
In contrast to heart rate, skin temperature (reflecting cutaneous
vascular tone) declined and rose in association with changes in blood
nicotine concentrations, showing no evidence of tolerance.

The above studies indicate rapid development of tolerance to some
(but not all) actions of nicotine in people. These studies were
performed with cigarette smokers who had abstained from smoking
the night before the study. Since significant quantities of nicotine
persist in the body even after overnight abstinence, there is probably
some persistence of tolerance. Experimental data supporting this
conclusion were obtained in a study of cardiovascular responses to
infused nicotine in smokers following either an overnight or 7-day
tobacco abstinence (Lee, Benowitz, Jacob 1987). Heart rate and blood
pressure responses were significantly greater after more prolonged
abstinence. However, within 60 to 90 min, the blood concentra-
tion-effect relationship in subjects after brief abstinence approxi-
mated that observed after prolonged abstinence. Thus, a significant
level of tolerance persists throughout the daily smoking cycle, but is
lost with prolonged abstinence. Tolerance, at least after abstinence
for one week, is rapidly reestablished with subsequent exposure.

48


Animal Studies

Many studies demonstrate that acute tolerance or tachyphylaxis
develops very quickly to actions of nicotine. Barrass and coworkers
(1969) demonstrated that pretreatment of mice with a single i.v. dose
(0.8 mg/kg) of nicotine resulted in an increase in the LD,, (dose
which is lethal to 50 percent of animals) for nicotine. Maximal
protection was seen 5 min after the injection, but this protection
diminished steadily over the next hour. Tachyphylaxis develops to
the effects of nicotine on locomotor activity. Stolerman, Bunker, and
Jarvik (1974) noted that pretreating rats with a 0.75-mg/kg dose of
nicotine 2 hr before challenge doses of nicotine (0.25 to 4.0 mg/kg)
resulted in a shift of the nicotine dose-response curves, indicating
reduced sensitivity. The ED,, values (doses that are effective in
producing the measured response in 50 percent of animals) for
nicotine-induced decreases in locomotor activity were nearly 2.4-fold
greater in nicotine-pretreated rats than in saline-pretreated animals.
Nicotine pretreatment also results in tachyphylaxis to the effects of
nicotine on body temperature (hypothermia) in cats (Hall 1972),
water-reinforced operant responding in rats (Stitzer, Morrison,
Domino 1970), discharge of lateral geniculate neurons of cats
(Roppolo, Kawamura, Domino 1970), repolarization of sartorius
muscle in frogs (Hancock and Henderson 19721, blood pressure
elevation in rats (Wenzel, Azmeh, Clark 19711, contraction of aortic
strips in rabbits (Shibata, Hattori, Sanders 1971), respiratory stimu-
lation in cats (McCarthy and Borison 19721, and gastrointestinal
contraction in squid (Wood 1969) and guinea pigs (Hobbiger, Mitchel-
son, Rand 1969). More recent studies have demonstrated that
pretreatment with as little as one dose of nicotine will attenuate
nicotine-induced elevations of plasma corticosterone (Balfour 1980)
and adrenocorticotropic hormone (ACTH) (Sharp and Beyer 1986)
levels in rats (see also Chapter III).

The interval between the pretreatment and challenge doses of
nicotine is a critical factor that determines whether tachyphylaxis is
observed. Aceto and coworkers (1986) examined the effect of iv.
nicotine infusion on heart rate and blood pressure in the rat.
Tolerance did not develop when the interval between pretreatment
and challenge doses was 30 min; marked tolerance was detected
when the interval was reduced to 1 min. However, Stolerman, Fink,
and Jarvik (1973) observed that after a single intraperitoneal dose of
nicotine to rats, acute tolerance to a second dose did not become
maximal until 2 hr after the initial injection.

Mechanisms of Tachyphylaxis

Although tachyphylaxis has been described for a wide variety of
nicotine's effects, very little is known about mechanisms. A nicotine

49


metabolite may play a role in the development of tachyphylaxis.
Barrass and colleagues (1969) argued that nicotine metabolites may
block nicotine receptors and thereby antagonize nicotine's lethal
effects. This argument was made because pretreatment with nic-
otine-N'-oxide protected mice from the lethal effects of large doses of
nicotine. LD,, values were increased approximately ninefold by
pretreatment with nicotine-N'-oxide. These authors hypothesized
that this protection may involve conversion of nicotine-N'-oxide to
hydroxynicotine. Their results indicated that injection of a reduction
product of cotinine, believed to be hydroxynicotine, gave immediate
protection, whereas maximum protection was not seen until 40 min
after injection of nicotine-N'-oxide. Thus it appears that metabolism,
possibly to hydroxynicotine, is required for the protective action of
nicotine-N'-oxide.

Another hypothesis is that tachyphylaxis is the result of desensiti-
zation of nicotine receptors. Desensitization of the receptor involves
a conformational change that results in increased affinity of the
nicotinic receptor for agonists coupled with decreased ability of the
receptor to transport ions (Weiland et al. 1977; Sakmann, Patlak,
Neher 1980; Boyd and Cohen 1984). Desensitization of nicotinic
receptors at the motor end-plate was first described by Katz and
Thesleff (1957) and has since been studied by a large number of
investigators, using either skeletal muscle or the electric organs of
the eel, Torpedo californica. Although tachyphylaxis has been
commonly suggested as being due to desensitization of brain
nicotinic receptors, the role of desensitization in tachyphylaxis to
specific behavioral effects of nicotine has not been studied. This is
because concentrations of nicotinic receptors in specific areas of the
brain corresponding to the behavioral effects being measured are not
high enough to use available methods.

Chronic Tolerance
Human Studies

Chronic tolerance to tobacco and nicotine has not been studied
systematically in human subjects, but it is clear, as noted previously,
that some tolerance does develop. Tolerance is not complete;
symptoms of nicotine toxicity such as nausea appear when smokers
increase their normal tobacco consumption by as little as 50 percent
(Danaher 1977).

These findings are consistent with the observations that smokers
increase their tobacco consumption and intake of nicotine with
experience. Such escalating dose patterns may be observed for
several years after initiation of either cigarette smoking or smok-
eless tobacco use. Cigarette smokers may achieve such increases by
augmenting the number of cigarettes smoked and by increasing the
amount of nicotine extracted from each cigarette. For users of

50


smokeless tobacco, switching to products with greater nicotine
delivery may also contribute to nicotine dose escalation (US DHHS
1986).

Animal Studies

Animal studies have proved useful in establishing the actual
development of tolerance to nicotine, the magnitude of such toler-
ance, and mechanisms that underlie this tolerance. The majority of
these studies have used the rat and mouse as experimental subjects.

Most of the chronic tolerance studies using the rat have focused on
the effects of nicotine on locomotor activity. Depression of locomotor
activity typically occurs following the injection of nicotine in doses
exceeding 0.2 mg/kg in drug-naive rats. Tolerance to this depression
develops following chronic treatment (Keenan and Johnson 1972;
Stolerman, Fink, Jarvik 1973; Stolerman, Bunker, Jarvik 1974). The
magnitude of this tolerance is influenced by the dose and dosing
interval. Tolerance persists for greater than 90 days when nicotine is
injected chronically. Tolerance to the effects of injected nicotine on
depression of locomotor activity could also be produced with nicotine
administered in the rats' drinking water or through subcutaneously
implanted reservoirs (Stolerman, Fink, Jarvik 1973).

Under certain experimental conditions, rats treated chronically
with nicotine exhibit an increase in locomotor activity following
nicotine challenge (Morrison and Stephenson 1972; BaA5ttig et al.
1976; Clarke and Kumar 1983a,b). A careful analysis of the response
to an acute challenge dose of nicotine demonstrated that soon after
the first dose of nicotine, depressed locomotor activity was observed;
after 40 min or more, increased locomotor activity became apparent
(Clarke and Kumar 1983b). Chronically injected rats exhibited this
enhanced activity progressively earlier postinjection. More recently,
Ksir and others (1985, 1987) demonstrated that chronic nicotine
injections may result in enhanced locomotor activity immediately
after nicotine injection if the rats were acclimated to the test
apparatus for 1 hr before nicotine injection. These findings indicate
that in the rat, tolerance develops to the depressant effects of
nicotine and that this tolerance uncovers a latent stimulatory action.

If mice are injected chronically with nicotine, tolerance develops to
the locomotor depressant effects elicited by a challenge dose of
nicotine (Hatchell and Collins 1977). The degree and rate of
development of tolerance appear to be influenced by the sex, as well
as the strain, of the animals. Tolerance development has been
studied by continuously infusing mice of several inbred strains with
nicotine and assessing tolerance by measuring locomotor activity,
body temperature, respiratory rate, heart rate, and acoustic startle
response following nicotine challenge. Such studies have demon-
strated that: (1) Tolerance to nicotine increases with the nicotine

51


infusion dose (Marks, Burch, Collins 1983a); (2) Tolerance is specific
for nicotinic cholinergic agonists in that nicotine-infused animals are
not cross-tolerant to the muscarinic cholinergic agonist oxotremo-
rine (Marks and Collins 1985); (3) Maximal tolerance is attained
within 4 days following the initiation of infusion and is lost within 8
days following the cessation of infusion (Marks, Stitzel, Collins 1985);
(4) Tolerance development varies between inbred mouse strains, with
some strains exhibiting marked tolerance and other strains showing
very little (Marks, Romm et al. 1986); and (5) Mouse strains that fail
to develop tolerance to nicotine are also relatively insensitive to the
effects elicited by an acute injection of nicotine (Marks, Stitzel,
Collins 1986). More recently these investigators compared the effects
of continuous and pulse infusions of nicotine on tolerance develop-
ment (Marks, Stitzel, Collins 1987). Pulse infusion was used to
simulate the conditions obtained when tobacco is smoked. Although
the total dose infused was the same in continuously infused and
pulse-infused animals, marked differences in tolerance were seen.
The pulse-infused animals exhibited a greater degree of tolerance.
The degree of tolerance was most correlated with peak nicotine
concentrations.

Chronic nicotine administration results in tolerance to a number
of other nicotinic effects. Tolerance develops to depression of operant
responding elicited by high doses of nicotine, such that after
sufficient chronic t.reatment, enhanced rather than depressed oper-
ant responding is seen (Clarke and Kumar 1983c; Hendry and
Rosecrans 1982). Attenuation of the effects of nicotine on electroen-
cephalogram (EEG) activity is seen in the rat following chronic
injection (Hubbard and Gohd 1975). These altered EEG responses
paralleled the development of tolerance to behavioral effects de-
scribed by these authors as "arousal." In contrast to the findings of
Hubbard and Gohd (1975), other studies indicate that chronic
tolerance does not develop to the behavioral stimulation effect of
nicotine (Battig et al. 1976; Morrison and Stephenson 1972; Clarke
and Kumar 1983a,c). Likewise, little or no tolerance to nicotine-
induced prostration after i.v. administration was observed after
chronic exposure in rats (Abood et al. 1981, 1984).

In addition, tolerance has been reported to develop to nicotine-
induced increases in plasma corticosterone, but not adrenal catechol-
amine release in rats (Balfour 1980; Van Loon et al. 1987). Anderson
and colleagues (1985) studied the effects of chronic exposure to
cigarette smoke on neuroendocrine function of the rat hypothala-
mus. These researchers observed that chronic exposure to cigarette
smoke over a period of 9 days did not result in tolerance to the ability
of acute intermittent exposure to cigarette smoke to reduce serum
levels of prolactin, luteinizing hormone, and follicle stimulating
hormone.

52


Mechanisms of Chronic Tolerance

Chronic tolerance to drugs may be due to an increase in the rate of
drug metabolism or to a decrease in sensitivity of the tissue to the
drug. Considerable differences exist among humans in the rate of
nicotine metabolism (Benowitz et al. 1982). Metabolism is faster
(shorter half-life) in smokers than in nonsmokers (Schievelbein et al.
1978; Kyerematen et al. 1982; Kyerematen, Dvorchik, Vesell 1983).
The contribution of enhanced nicotine metabolism to the develop-
ment of nicotine tolerance in humans is unclear. Studies of rats
which clearly demonstrate that chronic nicotine treatment results in
tolerance to nicotine also indicat,e that chronic nicotine administra-
tion does not increase the rate of nicotine metabolism in rats
(Takeuchi, Kurogochi, Yamaoka 1954) or mice (Hatchell and Collins
1977; Marks, Burch, Collins 1983b). These findings indicate that
tolerance to nicotine primarily involves reduced sensitivity of target
tissues.

Chronic tolerance to nicotine may be due to alterations in brain
nicotinic receptors (see Chapter III for further discussion of nicotine
receptors). At least two types of nicotinic receptors exist in rodent
brain (Marks and Collins 1982). One of these receptor types may be
measured with 3H-nicotine or `H-acetylcholine (3H-ACh) (Marks,
Stitzel et al. 1986; Martino-Barrows and Keller 19871, while the other
type may be measured with "`1-bungarotoxin (BTX). The nicotine-
binding site has higher affinity for nicotine than does the BTX site
(Marks and Collins 1982). Chronic nicotine injection, once or twice
daily for approximately 7 days, increased the number of 3H-nic-
otine/3H-ACh-binding sites in the brain (Ksir et al. 1985, 1987;
Morrow, Lay, Creese 1985; Schwartz and Kellar 1983, 1985). This
increase in nicotine-binding sites appeared to correlate with the
emergence of nicotine-induced increases in locomotor activity in the
rat. Studies of tolerance to nicotine in one inbred mouse strain (DBA)
also demonstrated that chronic nicotine treatment elicits an increase
in the number of brain nicotinic receptors as measured with both 3H-
nicotine and BTX as the ligands (Marks, Burch, Collins 1983a; Marks
and Collins 1985; Marks et al. 1985, 1986; Marks, Stitzel, Collins
1985,1986, 1987). These studies have also shown that the number of
3H-nicotine-binding sites increases at lower doses of nicotine than do
the BTX-binding sites. An increase in 3H-nicotine binding (Marks,
Burch, Collins 1983a) paraliels development of tolerance to various
responses during chronic infusion, In chronically infused DBA mice,
tolerance acquisition and disappearance parallel the up-regulation
and return to control, respectively, of brain 3H-nicotine binding
(Marks, Stitzel, Collins 1985). These findings suggest that the
increase in 3H-nicotine binding is related to the development of
tolerance to nicotine. However, further studies indicate that factors
other than receptor number must also be considered, because mouse

53


strains that do not develop tolerance to nicotine also demonstrate up-
regulation of nicotinic receptors following chronic infusion (Marks et
al. 1986; Marks, Stitzel, Collins 1986).

That chronic nicotine treatment results in a decrease in response
to the drug (tolerance) and an increase in the number of nicotinic
receptors was an unexpected finding. Marks, Burch, and Collins
(1983a) and Schwartz and Kellar (1985) have suggested that chronic
nicotine treatment results in chronic desensitization of nicotinic
receptors. Chronic desensitization of the nicotinic receptor is compa-
rable to chronic treatment with an antagonist and could be the
stimulus for up-regulation of the receptors. According to this
hypothesis, there is an increase in number of brain nicotinic
receptors but a decrease in the absolute number of "activatable"
(nondesensitized) receptors. This would result in a decreased re-
sponse to nicotine (tolerance). Marks and coworkers suggest that
inbred mouse strains failing to exhibit tolerance to nicotine, under
the procedures used by these investigators, have brain nicotinic
receptors that resensitize more rapidly than do those strains that do
exhibit tolerance.

By treating rats chronically with the acetylcholinesterase inhibi-
tor disulfoton, Costa and Murphy (1983) have found a decrease in rat
brain 3H-nicotine binding. Disulfoton-treated rats were also tolerant
to the antinociceptive effects of nicotine. Thus, tolerance to nicotine
effects may be seen when the number of nicotinic receptors is
increased or decreased by chronic drug treatment. The observation
that tolerance to at least one effect of nicotine can be obtained by a
technique that decreases brain nicotinic receptor numbers supports
the idea that chronic nicotine treatment results in an increase in the
total number of receptors but a decrease in those that may be
activated by nicotine; that is, a high fraction of the up-regulated
receptors are desensitized.

In contrast to the studies reviewed above, some investigators have
found no change in the number or affinity of 3H-nicotine-binding
sites in the brains of rats chronically exposed to nicotine (Abood et
al. 1984; Benwell and Balfour 1985).

Other potential neurochemical explanations for tolerance to
nicotine have been considered. Several reports (Westfall 1974;
Giorguieff et al. 1977; Arqueros, Naquira, Zunino 1978; Giorguieff-
Chesselet et al. 1979) indicate that nicotine stimulates dopamine
release in vitro, and a recent study demonstrated that nicotinic
agonists are less effective in stimulating dopamine release in slices of
striatum obtained from rats that had been chronically treated with
the nicotinic agonist dimethylphenylpiperazinium (DMPP) (Westfall
and Perry 1986). These findings are consistent with the idea that
chronic nicotinic agonist treatment results in a decrease in the
absolute number of receptors that can be activated.

54


Pharmacodynamics of Nicotine and Cigarette Smoking

As the foregoing review has shown, the intensity of nicotine's
effects is related to the dose given, the time since the last dose, and
the level of preexisting or acquired tolerance. Since nicotine can
produce effects that lead to further use (reinforcing effects! (Hen-
ningfield and Goldberg 1983, and can also produce effects that limit
use (aversive effects, usually at higher dose levels) (Danaher 19771,
the strength of the effect of a given dose can determine whether
more or less nicotine will be subsequently taken. Thus, factors such
as tolerance can affect the manner in which nicotine controls
behavior (Chapter IV). Similarly-, an individual's ability to develop
tolerance to the toxic actions may be critical in determining whether
smoking will occur and, if smoking is initiated, whether there will be
an increase in the number of cigarettes consumed each day.

Pharmacodynamic considerations may help explain the pattern of
cigarette smoking throughout the da)-. Intervals between smoking
cigarettes may be determined at least in part by the time required
for tolerance to disappear. With regular smoking there is accumula-
tion of nicotine in the body resulting in a greater level of tolerance.
Transiently high brain levels of nicotine following smoking individu-
al cigarettes may partially overcome tolerance. But the effects of
individual cigarettes tend to lessen throughout the day. Overnight
abstinence allows considerable resensitization to effects of nicotine,
and the daily smoking cycle begins again.

Pharmacodynamic observations with i.v. dosing of nicotine explain
the pattern of cardiovascular changes observed in cigarette smokers.
That brief infusions of nicotine increase heart rate to a maximum
suggests that heart rate will increase most with the first few
cigarettes of the day, but subsequently will not vary in relation to
the amount of nicotine consumed. That only partial tolerance
develops to heart rate acceleration due to nicorine suggests that
effects on heart rate may persist as long as significant levels of
nicotine persist, including overnight. These predictions were con-
firmed in a study in which volunteer cigarette smokers smoked
either high- or low-yield nonfilter research cigarettes or abstained
from smoking (Benowitz, Kuyt. Jacob 1984). Full compensation for
the low-yield research cigarettes, which contained only small
amounts of nicotine, was impossible. Resultant nicotine blood levels
were different by fourfold. As predicted, heart rate (assessed by
continuous ambulatory electrocardiogram (EKG) monitoring) in-
creased in the morning-more on smoking than nonsmoking days-
and the increase occurred with the first few cigarettes of the day.
Subsequently, heart rate followed a normal circadian pattern, but
was always higher during smoking than during abstinence. Also, as
predicted, heart rate was no different during the smoking of low-

55


yield or high-yield cigarettes, despite the fourfold difference in blood
nicotine concentration.

Pharmacodynamic aspects of the actions of nicotine may explain
in part how cigarette smoking causes coronary heart disease (US
DHHS 1983). As noted before, because of the accumulation of
nicotine and its dose-response characteristics, heart rate is increased
during cigarette smoking for 24 hr a day. Plasma catecholamine
concentrations and urinary catecholamine excretion remain in-
creased as well (Benowitz 1986c), consistent with the theory that
cigarette smoking produces sympathetic neural activation 24 hr each
day. Persistent sympathetic activation could result in the following
effects: (1) Alteration in lipid metabolism, resulting in a more
atherogenic lipid profile; (2) Promotion of platelet aggregation and
hypercoagulability; (3) Induction of vasoconstriction and coronary
spasm; and (4) Increased heart rate and myocardial contractility,
thereby an increase in the oxygen demands of the heart and of
circulating catecholamines, which can promote cardiac arrhythmias.
These factors could accelerate atherosclerosis and contribute to
acute myocardial infarction in a person with preexisting coronary
atherosclerosis (Benowitz 1986a) (see also Appendix B). There is no
apparent correlation between acute coronary events and the time at
which a person smokes a cigarette, perhaps because of the persistent
effects of nicotine throughout the day.

Constituents of Tobacco Smoke Other Than Nicotine With
Potential Behavioral Effects

Tobacco smoke contains more than 4,000 constituents, many of
which may have biological activity (US DHHS 1983). Although
nicotine is the major pharmacologic factor which determines the use
of tobacco, other constituents may also be involved. The behavioral
effects of tobacco constituents other than nicotine are described in
the Section below and in Chapter IV. This Section focuses more on
the chemicals that may be involved, whereas Chapter IV focuses
more on cigarette smoking behavior.

Minor Tobacco Alkaloids

Most of the research on the minor tobacco alkaloids has been
directed to determining physiological effects, such as the effect on
blood pressure and other cardiovascular responses and toxicological
effects, rather than the potential for behavioral effects. The pharma-
cologic effects of alkaloids of the nicotine group have been discussed
by Bovet and Bovet-Nitti (1948) and Clark, Rand, and Vanov (1965).
Nornicotine and anabasine were found to have qualitatively similar
actions but to be less potent than nicotine. Larson and Haag (1943)

56


reported that the potency of nornicotine as determined by effects on
blood pressure in dogs was about one-twelfth that of nicotine.

Nicotine analogs have been studied for discriminative stimulus
effects by using animal models (Chance et al. 1978) (see also Chapter
IV). The only chemical shown to produce a positive response in that
test system was 3-methylpyridylpyrrolidine. Recent research has
focused on binding at specific brain receptor sites. Martin and
coworkers compared binding characteristics of nicotine-related com-
pounds (Martin et al. 1986; Sloan et al. 1985). Lobeline, anabasine,
and cytisine were evaluated for effects on heart rate, blood pressure,
respiration rate, minute volume, and tidal volume (Sloan et al. 1987).
Lobeline and anabasine bound to low-affinity sites in the brain,
whereas cytisine bound only at a high-affinity site. The binding data
are consistent with the pharmacologic data, indicating that lobeline
and anabasine have different pharmacologic actions than cytisine.
Kanne and others (1986) and Abood and Grassi (1986) evaluated two
nicotine analogs, including a new radioligand, to study brain
nicotinic receptors. Kachur and others (1986) studied the pharmaco-
logic effects of a bridged-nicotine analog (methylene bridge between
the methyl of the pyrrolidine ring and the a-position of the pyridine
ring). The magnitude of pressor effect depended on the particular
enantiomer and dosage. These results emphasize that compounds
other than nicotine may act at the nicotine receptors; however, there
may be subpopulations of receptors to which different agonists and
antagonists bind (Chapter III).

N-Methylated derivatives of nicotine, including nicotine isometho-
nium ion IN-methylnicotinium ion, NMNj, have been shown to have
pressor and neuromuscular effects in some species (Shimamoto et al.
1958). Nicotine isomethonium ion was first reported to be a
metabolite of nicotine present in smokers' urine by McKennis and
coworkers in the 1960s and its presence in smokers' urine has been
recently confirmed (Neurath et al. 1987). Recently Crooks and
coworkers (Cundy, Godin, Crooks 1985) have shown that only the (Rj-
isomer of nicotine is converted to nicotine isomethonium ion in vitro
in guinea pig tissue homogenates or in vivo in guinea pigs.
Consequently, it is uncertain as to whether the nicotine isomethoni-
urn ion present in smokers' urine arrives from the small amount of
(Rj-nicotine present in tobacco smoke, or whether the human enzyme
systems have different specifications than the guinea pig enzymes.
Because little if any nicotine isomethonium ion penetrates the blood-
brain barrier (Pool 1987; Aceto et al. 1983j, it would appear that this
met.abolite could have behavioral actions only if it were formed in
the CNS. These findings emphasize the complexity of the pharmacol-
ogy of nicotine-related compounds. It can be concluded from research
on these compounds that some do bind to specific brain receptors and
may result in centrally mediated physiological changes. However,

57


there is inadequate evidence to date that any of these compounds
produces either aversive or rewarding effects in human smokers.

"Tar" and Selected Constituents of Tobacco Smoke Which
Contribute to Taste and Aroma

"Tar" is used to describe the dry particulate matter without t,he
nicotine in tobacco smoke ~Pillsbury et al. 1969). The possible role of
tar in t.he maintenance of the cigarette smoking habit has been
considered. Goldfarb and coworkers (19761 studied the effects of the
tar cont.ent (determined by cigarette smoking machine testing) on
the subjective reactions to cigarette smoking. Ratings of strength
were not related to the tar index of the cigarettes. The results were
interpreted as indicating that tar did not have a role in the
maintenance of cigarette smoking behavior. In a later study, Sutton
and coworkers (1982) found that when nicotine yield was held
constant, smokers of lower-tar cigarettes puffed more smoke and had
higher drug plasma levels. These results suggested that smokers
were compensating for reduced delivery of tar by inhaling a greater
volume of smoke. Because these two studies used different experi-
mental designs, it is difficult to draw a conclusion as to the role of tar
in relation to smoking behavior. However, based on knowledge about
the taste and aroma constituents of cigarette smoke, it is likely that
some of the chemicals in the tar fraction contribute to tobacco use, if
only by providing distinct sensory stimuli (Chapter VI). Consistent
with this possibility, minimal levels of tar are held by tobacco
manufacturers to be important to the taste characteristics of tobacco
smoke.

Several thousand compounds have been isolated from tobacco and
tobacco smoke (Dube and Green 1982), and many of these may be
biologically active (IARC 1986). The precursors to the carotenoids
and diterpeniods, selected nitrogenous and sulfur constituents,
waxes and lipids, and phenolics and acids contribute to the taste and
aroma of tobacco (Enzell and Wahlberg 1980: Heckman et al. 1981;
Davis, Stevens, Jurd 19763. A number of the isoprenoid corripounds
that. influence the taste and aroma of smoke may be formed by
sequential oxidation, rearrangement, and reduction reactions (Davis,
Stevens, Jurd 1976). Enzell and Wahlberg (1980) described several
norisoprenoid comp:iunds which are derived from the cyclic carot-
enoids and are important to smoke aroma. The particular taste and
aroma of a cigarette can be influenced by the selection of the grade
(quality and leaf position on the plant! and type of tobacco used in
the blend.

Taste and smell receptors in the pharynx, larynx, and nose provide
the first sensory input to the smoker as he or she lights up, an
experience which is generally perceived as pleasurable (Rose et al.
1985). The taste and smell of tobacco smoke may be important


reinforcers for tobacco smoking (Jarvik 1977tat least following
repeated association with the reinforcing effects of nicotine adminis-
tration (Chapter VII. By such behavioral conditioning, sensory cues
provided by tar and flavor additives could come to control the
tobacco-consuming behavior of the tobacco user. Changes in smoking
patterns when brands are switched and brand selection may be a
response in part to the particular flavor and aroma of the product
(Thornton 19781.

Carbon Monoxide

The mainstream and sidestream carbon monoxide (CO) deliveries
of cigarettes are influenced by cigarette design and puffing charac-
terist.ics of the smokers. Depending upon these factors, the main-
stream delivery usually ranges from 10 to 20 mg/cigarette. In a
study of 29,000 blood donors in 18 locations around the United
States, smokers were found to have median carboxyhemoglobin
(COHb) levels ranging from 3.2 to 6.2 percent (Stewart et al. 1974).
Anderson, Rivera, and Bright (1977) found the COHb levels in 50
smokers to vary from 3.9 to 14.0 percent, with the mean of 8.1
percent. The mean increment in COHb immediately after smoking 1
cigarette was 0.64 percent. COHb levels gradually decrease in blood
after cessation of smoking. Carbon monoxide is eliminated in expired
air. The rate of elimination depends on pulmonary blood flow and
ventilation. The half-life of COHb is 2 to 4 hr during daytime hours,
but as COHb is related to the level of exercise, the half-life may be as
long as 8 hr during sleep (Wald et al. 1975). For these reasons, many
smokers awaken in the morning with substantial levels of COHb,
despite not smoking overnight (Benowitz, Kuyt, Jacob 1982). Persons
smoking cigarettes with lower nicotine and CO yields have only
slightly lower levels of COHb when compared with those smoking
higher-yield products (Wald et al. 1980, 1981; Sutton et al. 1982; Hill,
Haley, Wynder 1983; Benowitz, Jacob, Yu et al. 1986).

Benowitz and colleagues (1986) studied tar, nicotine, and CO
exposure in smokers switched from their usual brand to low-, high-,
and ultra-low-yield cigarettes. This study indicated that there were
no differences in exposure comparing low- and high-yield, but tar
and nicotine exposure were reduced by about 50 percent and CO by
36 percent while smoking ultra-low-yield cigarettes. Switching from
a high to lower yield cigarette does not significantly reduce blood
COHb although switching to ultra low cigarettes has been shown to
lead to a significant reduction.

The toxic effects of high CO levels are well documented (US DHHS
1983). Some studies have tried to determine whether CO levels in the
blood similar to those observed in smokers can affect behavior. Beard
and Wertheim (1967) and Wright, Randell, and Shephard (1973)
reported performance decrements with COHb levels below 5.0

59


percent; however, Guillerman, Radziszewski, and Caille (1978) found
no psychomotor performance effects at COHb levels of 7 and 11
percent. Thus, the data are inconclusive with regard to the possible
influence of CO on psychomotor performance at levels normally
encountered in smokers.

Acetaldehyde and Other Smoke Constituents

Acetaldehyde is a major constituent of tobacco smoke, with
mainstream smoke levels in commercial cigarettes ranging from 0.5
to 1.2 mg/cigarette (IARC 1986). The delivery of volatile aldehydes is
influenced by cigarette design, with reductions achieved by specific
filtration and air dilution techniques. Yields over 5.9 mg have been
reported for large cigars (Hoffmann and Wynder 1977). Acetalde-
hyde is the primary metabolite of ethanol, and its toxic potency is 20
to 30 times that of ethanol. Acetaldelhyde has been suggested to
have an adverse effect on the heart (James et al. 1970). Acetaldehyde
and acrolein, another important aldehyde in the gas phase of
cigarette smoke, activate the sympathetic nervous system (Egle and
Hudgins 1974). Acetaldehyde, by releasing norepinephrine, results
in a pressor effect (Kirpekar and Furchgott 1972; Green and Egle
1983). Depressor effects occur at high doses of the aldehydes in
guanethidine-pretreated hypertensive rats. Frecker (1983) indicated
that condensation products of acetaldehyde may be active on
endogenous opioid systems. Torreilles, Guerin, and Previero (1985)
reviewed the synthesis and biological properties of beta-carbolines,
the condensation products of tryptophan and indole alkylamines
with aldehydes. Beta-carbolines occur as plant constituents, includ-
ing minor constituents in tobacco. For example, harman (l-methyl+-
carboline) has been identified in tobacco and tobacco smoke (Snook
and Chortyk 1984). Carbolines from other plant species have been
used as hallucinogens. The research conducted to date indicates a
potential pharmacologic effect of the aldehydes, especially with
regard to cardiovascular physiology; however, the evidence is
inadequate to determine if these volatile smoke constituents in the
doses delivered in tobacco smoke contribute to the behavioral effects
of cigarette smoking.

Summary and Conclusions

1. All tobacco products contain substantial amounts of nicotine
and other alkaloids. Tobaccos from low-yield and high-yield
cigarettes contain similar amounts of nicotine.
2. Nicotine is absorbed readily from tobacco smoke in the lungs
and from smokeless tobacco in the mouth or nose. Levels of
nicotine in the blood are similar in people using different forms
of tobacco. With regular use, levels of nicotine accumulate in


the body during the day and persist overnight. Thus, daily
tobacco users are exposed to the effects of nicotine for 24 hr
each day.

3. Nicotine that enters the blood is rapidly distributed to the
brain. As a result, effects of nicotine on the central nervous
system occur rapidly after a puff of cigarette smoke or after
absorption of nicotine from other routes of administration.
4. Acute and chronic tolerance develops to many effects of
nicotine. Such tolerance is consistent with reports that initial
use of tobacco products, such as in adolescents first beginning
to smoke, is usually accompanied by a number of unpleasant
symptoms which disappear following chronic tobacco use.

61


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CHAPTER III

NICOTINE: SITES AND
MECHANISMS OF ACTIONS

75


CONTENTS

Overview .............................................................. .79
  Peripheral Effects of Nicotine ............................. .79
  Central Sites of Nicotine Actions ........................ .80
  Neuroendocrine Effects of Nicotine ...................... .81
  Electrophysiological Effects of Nicotine ................ .81

D

listribution and Cerebral Metabolic Effects of
Nicotine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82
Distribution of Nicotine,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82
    Tissue Distribution of Nicotine: Time Course
      and Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . .82
   Heterogeneity of Nicotine Uptake: Microauto-
    radiographic and Subcellular Studies.. . . . . . . . . .85
Effects of Nicotine on Cerebral Metabolism . . . . . . . . . . .85

Nicotine Receptors ................................................. .88
  Peripheral Nicotine Receptors ............................. .88
  Radioligand Binding to Putative Nicotine Choliner-
   gic Receptors in Mammalian Brain ................... .89
    Agonist Binding ......................................... .89
    Radioligand Binding ................................... .91
    Antagonist Binding .................................... .91
  Functional Significance of Nicotinic Binding Sites .. .92
    High-Affinity Agonist Binding Sites .............. .92
    Alpha-Bungarotoxin Binding Sites ................. .92
    Behavioral and Physiological Studies ............. .93
  The Neuroanatomical Distribution of Nicotinic
  Binding Sites in the Brain .............................. .93
    High-Affinity Agonist Binding Sites .............. .93
       Rodent .................................................. .93
     Monkey ................................................. -94
       Human ................................................. .94
    Alpha-Bungarotoxin Binding Sites ................. .94
     Molecular Biology ...................................... .95
  Central Nicotinic Cholinergic Receptors: Pre- or
   Postsynaptic?. ................................................ .95
    Presynaptic Regulation of Neurotransmitter
      Release .................................................. -95
    Somatodendritic Postsynaptic Actions ............ .95

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Neuroendocrine and Endocrine Effects of Nicotine ....... .95
  Cholinergic Effects ............................................ .96
  Modulation of Catecholamine and Serotonin
   Activity ......................................................... 97
     Effects  on Serotonergic Neurons ................... .99
    Effects on Catecholaminergic Neurons .......... 100
  Stimulation of Pituitary Hormones ..................... 101
    Arginine Vasopressin ................................. 102
    The Pro-Opiomelanocorticotropin Group of
      Hormones ............................................. 103
  Thyroid .......................................................... 104
  Adrenal Cortex ............................................... 104
  Androgens ...................................................... 106
  Estrogens ....................................................... 106
Pancreas and Carbohydrate Metabolism .............. 107

Electrophysiological Actions of Nicotine .................... 107
  Electrocortical Effects ....................................... 107
  Spontaneous Electroencephalogram ..................... 108
  Sensory Event-Related Potentials ........................ 112
  Cognitive Ever&Related Potentials ...................... 114
  Motor Potentials .............................................. 115

Other Peripheral Effects Relevant to Tobacco Use.. . , . .115
Psychophysiological Reactivity and Smoking.. . . . . . . . 116
Psychophysiological Reactivity, Smoking Cessation,
  and Relapse.................................................120

Summary and Conclusions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

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Overview

Nicotine, in tobacco smoking concentrations, is a powerful psy-
choactive drug (Domino 1973; Kumar and Lader 1981; Balfour 1984). A
wide variety of stimulant and depressant effects is observed in
animals and humans that involves the central and peripheral
nervous, cardiovascular, endocrine, gastrointestinal, and skeletal
motor systems. These heterogeneous effects, along with behavioral
and psychological variables, result in self-administration of tobacco,
tobacco dependence, and withdrawal phenomena with abrupt cessa-
tion of tobacco smoking. This Chapter discusses sites and mechan-
isms of nicotine actions that may help to explain why tobacco
products are self-administered.

The first Section of this Chapter provides general summaries of
several major effects of nicotine in the body. Following this broad
overview, the Chapter presents detailed discussions of sites and
mechanisms of nicotine action that may be particularly important to
understand tobacco use. Tissue distribution of nicotine, cerebral
metabolic effects, and nicotine receptor binding are reviewed. Next,
neuroendocrine and endocrine effects of nicotine are discussed.
Then, electrophysiological effects of nicotine are presented. Finally,
the effects of smoking on psychophysiological reactivity are discuss-
ed.

Peripheral Effects of Nicotine

Nicotine exerts its action on the cardiovascular, respiratory,
skeletal motor, and gastrointestinal systems through stimulation of
peripheral cholinergic neurons via afferent chemoreceptors and
ganglia of the autonomic nervous system (ANSI (Ginzel 1967b).
Inasmuch as both sympathetic and parasympathetic ganglia are
stimulated by levels of nicotine derived from tobacco smoking, the
end result depends on the summation of the effects of autonomic
ganglion stimulation and reflex effects. The resulting peripheral
physiological changes generally resemble sympathetic nervous sys-
tem (SNS) arousal, but there are also some effects of nicotine and
smoking that lead to physiological relaxation. For example, there is
usually an increase in heart rate and blood pressure immediately
following cigarette smoking. In addition, there is cutaneous vasocon-
striction of the distal extremities. In contrast, nicotine can relax
skeletal muscles (e.g., reduce patellar reflex) in humans and animals
via effects on Renshaw cells (Domino and Von Baumgarten 1969;
Ginzel and Eldred 1972; Ginzel1987). But it also can enhance tension
in some muscles (e.g., trapezius muscle) (Fagerstrom and Gotestam
1977). Nicotine in small doses can enhance respiration through
stimulation of peripheral chemoreceptors. Yet, high nicotine doses
can cause respiratory failure. (See Appendix B for a discussion of

79


nicotine toxicity.) The gastrointestinal effects of nicotine are com-
plex, involving an increase in secretions and reduced motility for a
short period of time.

The peripheral actions of nicotine as a cholinergic agonist have
made it a valuable pharmacologic tool for studying nicotinic
cholinergic actions and functioning in many physiological systems.
This Chapter focuses on the mechanisms of nicotine's actions
relevant to tobacco use. Several peripheral actions of nicotine, for
instance muscular relaxation, may contribute to the habitual use of
tobacco products (see smoking and stress in Chapter VI). However,
because the central nervous system (CNS) actions of nicotine and
resulting neurochemical and electrical effects mediate subsequent
biological and behavioral responses, a review of these actions
contributes to an understanding of the reinforcing effects of nicotine.

Central Sites of Nicotine Actions

Nicotinic binding sites or receptors in the brain have been
differentiated as very high, high, and low affinity types (Shimohama
et al. 1985; Sloan, Todd, Martin 1984; Sloan et al. 1985). In the rat
brain, when cholinergic muscarinic receptors are blocked, the
autoradiographic distribution of 3H-acetylcholine (ACh) and "H-
nicotine are essentially identical (Clarke and Kumar 1984; Clarke,
Pert, Pert 1984). However, these brain binding sites differ from
peripheral nicotinic receptors in ganglia and skeletal muscle.

Chronic nicotine administration results in up-regulation in region-
al rat brain 3H-ACh binding sites measured in the presence of
atropine to block the muscarinic sites (Schwartz and Kellar 1985).
Up-regulation of 3H-nicotine binding sites also has been reported
after continuous nicotine infusions in mice (Marks, Burch, Collins
1983a). In contrast, most agonists that act on receptor sites in the
body, when given chronically, produce a reduction (or down-regula-
tion) in the number of receptors. Both Marks, Burch, and Collins
(1983b) and Schwartz and Kellar (1983, 1985) have suggested that
nicotinic cholinergic receptors undergo a functional blockade but
that sufficient recovery would allow enhanced behavioral responses
to low doses of nicotine to occur within 24 hr, as has been shown
behaviorally by Clarke and Kumar (1983) and Ksir and coworkers
(1985). This phenomenon may help to explain the tolerance to
nicotine that develops with repeated exposure. However, the time
course of changes in receptor number and other biological effects of
nicotine must be carefully compared to determine mechanisms
underlying tolerance. (See Chapter II for additional discussion.)

Several investigators have used in vitro autoradiography to
identify 3H-nicotine binding sites in the rat brain. These audioradio-
graphic binding studies suggest where nicotine is acting. London,
Waller, and Wamsley (1985) have found the most intense localization

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of 3H-labeled nicotine in the interpeduncular nucleus and medial
habenula.

Cerebral metabolism studies also suggest key sites of action.
London and colleagues (1985) have reported that nicotine stimulated
local cerebral glucose utilization (LCGU) by 139 percent over that of
the control in the medial habenula and by 50 to 100 percent in the
superior colliculus and the anteroventral thalamic and interpedun-
cular nuclei. Other areas of the brain showed moderate or no
significant changes. These effects of nicotine were blocked by
mecamylamine, a nicotinic recept,or antagonist, confirming that they
acted via nicotinic receptors. Furthermore, they correlated well with
the distribution of 3H-nicotine binding in the brain except in layer
IV of the neocortex, which showed nicotine binding but no change in
LCGU. Sites that show increased glucose utilization after nicotine
administration are probably functionally important loci of nicotinic
actions. When nicotine binding and increased energy utilization both
occur at a given site, it is likely to be involved in nicotine's actions.

Neuroendocrine Effects of Nicotine

Some of the actions of nicotine result from the release of ACh and
other neurotransmitters, including norepinephrine (NE). Nicotinic
cholinergic agonists including nicotine, carbachol, and 1,1-dimethyl4-
phenylpiperazinium (DMPP) release endogenous ACh from the
presynaptic cholinergic nerve terminals in addition to stimulating
postsynaptic nicotinic receptors (Chiou 1973; Chiou and Long 1969).
Nicotinic agonists also release ACh from rat cerebral cortical
synaptic vesicles and can release newly synthesized 3H-ACh from
synaptosomes prepared from the myenteric plexus of guinea pig
ileum and from mouse cortical synapses (Briggs and Cooper 1982;
Rowe11 and Winkler 1984). These effects are Ca"+-dependent and are
blocked by hexamethonium, a quarternary nicotinic receptor antago-
nist. In addition, nicotine-induced release of ACh in the hippocampal
synaptosomes is blocked by the ion channel blocker, histrionicotoxin
(Rapier et al. 1987). There is good evidence that nicotine releases
ACh by a presynaptic mechanism. In contrast, presynaptic musca-
rinic receptors, mostly of the M,-subtype, inhibit ACh release.
Nicotine administration increases the amounts of other chemicals in
the blood and brain, including serotonin, endogenous opioid peptides,
pituitary hormones, catecholamines, and vasopressin (Domino 1979;
Gilman et al. 1985; Marty and colleagues 1985). These chemicals may
be involved in reinforcing effects of nicotine (see Chapters IV, VI).

Electrophysiological Effects of Nicotine
Nicotine administration is accompanied by brain wave or electro-
encephalogram (EEG) activation in animals (Domino 1967). The EEG-
activating effects of small doses of nicotine occur in intact as well as

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brainstem-transected animals. Nicotine acts primarily directly on
brainstem neuronal circuits to produce these effects (Domino 1967).
However, stimulation of peripheral afferents (Ginzel 1987) and
release of catecholamines and possibly neurotransmitters and modu-
lators, such as serotonin or histamine, may enhance the direct
central effects of nicotine.

The EEG-activating effects of nicotine result in behavioral arousal
(Domino, Dren, Yamamoto 1967). In cigarette smokers, nicotine
produces sedat.ive and stimulant effects (Kumar and Lader 1981).
Aceto and Martin (1982) have reviewed the large variety of nicotine
effects on behavior including facilitation of memory, the increase in
spontaneous motor activity, nicotine's antinociceptive properties,
and its suppression of irritability. These behavioral and psychologi-
cal effects are discussed in Chapters IV and VI.

Distribution and Cerebral Metabolic Effects of Nicotine

Nicotine, administered by various routes, rapidly enters the brain
and also distributes to specific, peripheral organs. Nicotine produces
a distinct pattern of stimulation of cerebral metabolic activity that
suggests where nicotine acts in the brain. This Section reviews
studies on the distribution of nicotine after its administration to
experimental animals, data on the relationship between tissue levels
of nicotine and the drug's biological effects, and studies on mapping
the cerebral metabolic effects of nicotine in the rat brain.

Distribution of Nicotine

Tissue Distribution of Nicotine: Time Course and Other
Considerations

The distribution in the body of exogenously administered nicotine
has been a topic of interest for more than a century and has been
reviewed several times (Larson, Haag, Silvette 1961; Larson and
Silvette 1968, 1971). As early as 1851, Orfila described experiments
in which he detected nicotine in various organs (e.g., liver, kidney,
lungs) and in the blood of animals after nicotine administration. In
the 1950s the development of radiotracer methods led to a reexami-
nation of nicotine distribution in the body.

Werle and Meyer (1950) found that the brain, compared with other
organs, contained the highest nicotine levels immediately after
injection of a lethal dose in guinea pigs. Tsujimoto and colleagues
(1955) found a high concentration of nicotine in the brain after the
drug was administered to rabbits and dogs. Yamamoto (1955)
observed that 1 hr after a subcutaneous (s.c.) injection of 5 mg/kg in
the rabbit, the nicotine content was highest in the kidney. The
pancreas, ileum, ventricular muscle, skeletal muscle, lung, spleen,
cerebral cortex, omental fat, and liver showed progressively lower

82


levels of nicotine at 3 hr. None of the tissues had detectable levels at
6 hr. In the dog, the highest level at 1 hr was in the kidney, followed
by the pancreas, brain, ileum, liver and omental fat, spleen, heart,
muscle, and lung.

Schmiterlow and colleagues used radiolabeled nicotine and whole-
body autoradiography to study the distribution of nicotine in several
species (Hansson and Schmiterlow 1962; Appelgren, Hansson,
Schmiterlow 1962, 1963; Hansson, Hoffman, Schmiterlow 1964;
Schmiterlow et al. 1965; Schmiterlow et al. 1967). After radiolabeled
nicotine was administered, radioactivity representing nicotine and
its metabolites was concentrated in some organs, particularly the
brain. Hansson and Schmiterlow (1962) injected (Sl-nicotine-methyl-
`*C intramuscularly or intravenously (iv.) in mice. Within 5 min,
high concentrations were found in the brain, adrenal medulla,
stomach wall, and kidney. Lower concentrations were observed in
the liver, skeletal muscle, and blood, but all concentrations were
higher in tissue than in blood. Activity was high in the kidney from 5
min to 4 hr after the nicotine injection, with the highest activity
occurring within the first hour. The adrenal medulla maintained a
high concentration at 1 hr and 4 hr after injection, but little or no
activity was observed at 24 hr. At 30 min, the levels were high in the
walls of large blood vessels and in the bone marrow. Radioactivity
disappeared rapidly from the brain.

Appelgren, Hansson, and Schmiterlow (1962) prepared whole-body
autoradiograms of mice and cats given i.v. injections of 14C-nicotine.
An initial, heterogeneous accumulation of radioactivity occurred in
the CNS. Fifteen minutes after the radiotracer injection, the cat
brain showed distinctly more intense labeling of grey than of white
matter. Also apparent was a regional distribution within grey
matter areas, particularly in the hippocampus. By 30 min, radioac-
tivity was reduced. Studies of mice demonstrated a high concentra-
tion of label in the brain at 5 min. By 30 min, the concentration was
high in salivary glands, stomach contents, liver, and kidneys, while
the brain was almost devoid of radioactivity. The same group also
showed the accumulation of 14C-nicotine in the retina of the eye after
i.v. administration (Schmiterlow et al. 1965).

Fishman (1963) reported that in rats given randomly labeled 14C-
nicotine intraperitoneally (i.p.) and killed 3 hr later, the kidney
contained the highest concentration of radioactivity, followed by the
lung, liver, brain, skeletal muscle, spleen, and heart. In the dog,
more `%-nicotine was present in the stomach wall than in any other
tissue analyzed 3 hr after i.v. injection of radioactive nicotine.

Yamamoto, Inoki, and Iwatsubo (1967) gave mice S.C. injections of 5
mg/kg methyl-`4C-nicotine. Five minutes later, they found 0.5 to 1
pg/g (wet weight) of nicotine in various brain regions, including the
cerebral cortex, superior and inferior portions of the brain stem, and

83


the cerebellum. Highest levels were detected 5 to 10 min after
injection. Maximum levels in liver and whole blood were observed 2
and 10 min, respectively, after the injection.

Yamamoto, Inoki, and Iwatsubo (1968) studied penetration of 14C-
nicotine in rat tissues in vivo and in vitro. They found that 5 mg/kg,
i.p., in male Wistar rats produced the following maximum tissue-to-
blood ratios of 14C-nicotine activity after 10 to 20 min: kidney, 8.7;
liver, 6.7; submaxillary gland, 6.2; cerebral cortex, 3.5; brainstem,
2.4; and heart, 1.8. When they incubated tissue slices with 10e4 M 14C-
nicotine for 30 min at 37"C, the relative uptake of the label was
similar: kidney cortex, 2.6; liver, 2.1; submaxillary gland, 2.1; and
cerebral cortex, 2.0. Penetration in slices was unaffected by uncou-
pling oxidative phosphorylation or blocking metabolic pathways,
indicating that the uptake was not by active transport. In vivo,
tissue-to-blood ratios were greater than slice-to-medium ratios,
indicating that a process other than passive diffusion was involved.

Because the respiratory tract is a major route by which nicotine
from tobacco smoke enters the body, Schmiterlow and coworkers
(1965) sprayed 14C-nicotine solution directly onto the trachea of mice.
Autoradiograms from mice killed at 2 min exhibited a high amount
of radioactivity in the respiratory tract and lungs and showed that
nicotine enters the CNS rapidly by this route as well. At 15 min,
radioactivity still persisted in the lungs, was reduced in the brain,
and appeared in large amounts in the kidneys and stomach.

Uptake and distribution of nicotine from tobacco smoke have also
been assessed. Harris and Negroni (1965) exposed mice to cigarette
smoke and extracted nicotine from the lungs (5 to 25 pg). Mattila and
Airaksinen (1966) exposed guinea pigs to the smoke of one 4-g cigar
over a period of 40 min, with intermittent ventilation with fresh air,
and found that the same tissues which concentrated nicotine
administered by other routes also showed nicotine uptake from
smoke. Organ-to-blood ratios were lung, 2.0; spleen, 3.0; intestine,
2.9; and brain, 1.1.

The use of positron-emitting radiotracers permits in vivo estima-
tion of nicotine uptake into the brain and other organs, offering the
potential of eventually relating nicotine action in the living human
brain to behavioral and disease states. Maziere and coworkers (1976)
prepared (S)-nicotine-methyl-"C, which they administered by i.v.
injection to mice and rabbits. The time course of the radiotracer
confirmed earlier studies and showed a maximum concentration in
the 5 min following injection, except in the liver and spleen. Highest
radioactivity was in kidneys and brain, followed by liver and lungs.
The brain activity dropped rapidly, whereas the kidney concentra-
tion remained high (8 percent of injected dose) at 50 min after the
injection. External imaging by a y camera showed considerable

84


radioactivity in the head, kidneys, and liver. Brain activity decreased
sharply over 1 hr, while activity remained high in liver and kidneys.

Maziere and coworkers (1979) used "C-nicotine and positron
emission tomography (PET) in baboons and found that "C-nicotine
readily penetrated into the brain and then dropped sharply with
time. Radioactivity was high in the temporal lobe, cerebellum,
occipital cortex, pons, and medulla oblongata. There was also a high,
stable radioactivity level in the retina, consistent with the earlier
observation that radioactivity from `V-nicotine is found in the
retina after i.v. administration (Schmiterlow et al. 1965).

Heterogeneity of Nicotine Uptake: Microautoradiographic and
Subcellular Studies

Appelgren, Hansson, and Schmiterlow (1963) used a microautora-
diographic method to study the localization of nicotine within the
superior cervical ganglion of the cat. Most of the radioactivity was
localized in the ganglion cells, with little labeling of satellite cells
and connective tissue.

Schmiterlow and coworkers (19671, using microautoradiograms of
mouse brains after injection of 14C-nicotine and 3H-nicotine, reported
that nicotine is concentrated in nerve cells. Brain areas with a high
density of nerve cells, such as the molecular and pyramidal cell
layers of the hippocampus and the molecular layer of the cerebel-
lum, contained high amounts of radioactivity.

Yamamoto, Inoki, and Iwatsubo (1967) studied accumulation of
14C-nicotine into subcellular fractions (nuclear, mitochondrial, nerve
ending, microsomal, soluble) of mouse brain after i.p. injection of 5
mg/kg (20 $X/kg). Most of the radioactivity was in the soluble
fraction. Less than one-tenth of the radioactivity in the soluble
fraction was found in microsomes and nerve endings; however,
radioactivity levels in microsomes were somewhat higher than in
nerve endings.

Effects of Nicotine on Cerebral Metabolism

Following the demonstration that 3H-nicotine binds stereoselec-
tively and specifically in preparations of rat brain (Yoshida and
Imura 1979; Martin and Aceto 1981; Marks and Collins 19821, brain
binding sites were visualized (Clarke, Pert, Pert 1984) and quantified
(London, Waller, Wamsley 1985) by light microscopic autoradiogra-
phy. However, mapping nicotinic binding sites or identifying specific
binding sites for any drug or neurotransmitter does not necessarily
mean that receptors are coupled to pharmacologic actions. An
example of nonfunctional, stereoselective, specific binding is that of
3H-naloxone to glass fiber filters (Hoffman, Altschuler, Fex 1981). In
addition, because the brain is a highly interconnected organ, drugs

85


may produce effects in brain regions remote from their initial
receptor interactions. Receptor maps would show primary binding
sites but not sites where important secondary actions might occur.

Functional mapping procedures, such as the use of autoradio-
graphic techniques to measure rates of LCGU and regional cerebral
blood flow, are another way to determine the sites of the in vivo
effects of nicotine in the brain. The 2-deoxy-D-[1-`Y$$ucose (2-DG)
method for measuring LCGU (Sokoloff et al. 19771 has been used to
demonstrate a relationship between local cerebral function and
glucose utilization under a wide variety of experimental conditions,
including pharmacologic treatments (Sokoloff 1981; McCulloch
1982). The effects of acute, S.C. injections of nicotine on LCGU were
examined by London and colleagues (1985, 1986) and by London,
Szikszay, and Dam (1986), while Grunwald, Schrock, and Kuschinsky
(1987) measured the effects on LCGU of constant plasma levels of
nicotine produced by iv. infusion.

Subcutaneous injections of nicotine stimulated LCGU in specific
brain regions (Table 1, Figure 11, including portions of the visual,
limbic, and motor systems. Effects of nicotine infusion generally
paralleled those obtained with S.C. injections. The greatest increase
in response to S.C. nicotine occurred in the medial habenula. Marked
increases in LCGU were noted in the anteroventral thalamic
nucleus, interpeduncular nucleus, and superior colliculus. Moderate
increases were seen in the retrosplenial cortex, interanteromedial
thalamic nucleus, lateral geniculate body, and ventral tegmental
area. No significant effects were observed in the frontoparietal
cortex, lateral habenula, or central grey matter. LCGU responses to
S.C. injection of nicotine were completely blocked by mecamylamine,
indicating the specificity of nicotine effects.

The effects of nicotine on LCGU correlate well with the distribu-
tions of 3H-nicotine binding sites (Clarke, Pert, Pert 1984; London,
Waller, Wamsley 1985). Areas such as the thalamic nuclei, the
interpeduncular nucleus, medial habenula, and the superior collicu-
lus, where there is dense labeling with 3H-nicotine, show moderate to
marked nicotine-induced LCGU increases. Areas with less specific
binding show smaller LCGU responses to nicotine, and the central
grey matter, which lacks specific 3H-nicotine binding, shows no
LCGU response. Similarly, nicotine dramatically increases LCGU in
the medial but not the lateral habenula, reflecting different densities
of 3H-nicotine binding sites. In general, 3H-nicotine binding sites
visualized autoradiographically in the rat brain are functional
nicotine receptors. However, layer IV of the neocortex displays
significant 3H-nicotine binding, but lacks an LCGU response.

In most brain areas, significant LCGU stimulation was obtained
with 0.3 mg/kg of nicotine S.C. (London et al. 19861, a dose similar to
one used successfully in training rats to distinguish nicotine from

86


TABLE l.-R&Nicotine effects on glucose utilization in the
        rat brain

Local cerebral glucose utilization
(um01/100 g tissue!mmuteI

Brarn region               Saline control   Nxotine 11.7j mg!kgr

Prontopar1etal cortex. layer I\      110 2 8.1        108 t 6.5

Retrosplenml cortex. law I        98 i 6.5        123 + 5.1'

Thaiamlc nuclei

.L\nteroventral
Interantcromed~al

Lateral gemculatP body

Interpeduncular nucleus


Medial habenula


Supw7or colllculus

109 1 6.5        201 L 61'
125 i- 86        Ii5 t 12.3'


82 z 6.8        106 r 44'


99 -t 9.8        182 + 9.31


70 2 52        167 f 37'


72 i 52        142 f 4.6'

Central grey matter             66 2 4.0         77 f 4.3

FIGURE l.-Effect of subcutaneous R,S-nicotine (1 mg/kg, 2
       min before S-deoxyglucose) on
      autoradiographic grain densities, representing
      glucose utilization

saline in a T-maze apparatus (0.4 mg/kg, s.c.) (Overton 1969).
Nicotine-induced stimulation of LCGU in the ventral tegmental area

87


and the habenular complex (London et al. 1985, 1986) may relate to
the reinforcing properties of the drug (see Chapter IV). These regions
of the brain have been implicated in drug- and stimulation-induced
reward systems, respectively (Wise 1980; Nakajima 1984). Additional
studies, using specific conditions under which nicotine is reinforcing,
are needed to elucidate the anatomical loci involved in nicotine-
induced reward and to identify the neurophysiological mechanisms
by which nicotine acts as a reinforcer.

Nicotine Receptors

Nicotine exerts diverse pharmacologic effects in both the peripher-
al nervous system (PNS) and CNS. The peripheral actions of nicotine
are important, and some may reinforce the self-administration of
nicotine. For example, stimulation in the trachea (Rose et al. 1984)
seems to be involved in some of the pleasurable effects of smoking.
Skeletal muscle relaxation and electrocortical arousal, both stimu-
lated by actions of nicotine in the lung (Ginzel 1967a,b, 1975, 1987),
may contribute to habitual tobacco use (Chapter VI). However, it is
generally believed that the central actions of nicotine are of primary
importance in reinforcing tobacco use (Chapter IV). In animals, the
neuropsychopharmacologic effects of this drug are, with few if any
exceptions, mediated through central sites of action. These effects
are likely to contribute to the drug's reinforcing properties in
animals and humans (Clarke 1987b). In addition, the effects of
nicotinic antagonists on tobacco smoking in humans (Stolerman et
al. 1973) and in rhesus monkeys (Glick, Jarvik, Nakamura 1970)
suggest a central site of reinforcement, but do not rule out a
peripheral site. To understand these actions, it is important to know
exactly where nicotine acts in the body. This Section discusses
evidence for nicotine receptors.

Peripheral Nicotine Receptors

In the mammalian PNS, nicotine and muscarine mimic different
actions of ACh by acting at different types of cholinergic receptors.
Nicotinic cholinergic receptors (nAChRs) have been subdivided
according to location and sensitivity to nicotinic antagonists. Recep-
tors of the C6 or "ganglionic" type are found principally at
autonomic ganglia, in the adrenal medulla, and at sensory nerve
endings; nicotinic cholinergic transmission in autonomic ganglia is
selectively blocked by hexamethonium and certain other compounds.
Receptors of the "neuromuscular" type (sometimes referred to as
Cl0 type) are located on the muscle endplate, where transmission is
selectively blocked by compounds such as decamethonium and alpha-
bungarotoxin (a-BTX).

88


Higher doses of nicotine are required to stimulate nAChRs in
skeletal muscle than at autonomic ganglia. Ganglionic nAChRs
appear to be more sensitive than their neuromuscular counterparts,
not only to the stimulant but also to the desensitizing actions of
nicotine (Paton and Savini 1968). Doses of nicotine obtained by
smoking cigarettes do not appear to affect the muscle endplate
direct,ly. Therefore, if the CNS were to possess both types of nAChR,
doses of nicotine obtained by normal cigarette smoking might affect
only the CG-receptor population. Accordingly, many of the central
effects of nicotine in vivo and in vitro are reduced or blocked by
nicotinic antagonists that are CG-selective in the periphery. The
most widely used CG-selective antagonist is mecamylamine, which
passes freely into the CNS after systemic administration. Mecamyia-
mine ant.agonizes actions of nicotine in the brain and spinal cord, as
revealed by behavioral (Collins et al. 1986; Goldberg, Spealman,
Goldberg 1981) and electrophysiological experiments (Ueki, Koketsu,
Domino 1961) and also by studies of neurotransmitter release (Hery
et al. 1977; Chesselet 1984). There have been few attempts to
determine whether these central nicotinic actions are also blocked
by neuromuscular antagonists, while several studies support the
existence of central C6 nAChRs (Aceto, Bentley, Dembinski 1969;
Brown, Docherty, Halliwell 1983; Caulfield and Higgins 1983; Egan
and North 1986).

The search for putative central a-BTX nAChRs has been hindered
by several factors, including the central convulsant actions of a-BTX
antagonists (Cohen, Morley, Snead 1981) and the probable need to
deliver locally high concentrations of nicotine. Nevertheless, several
studies have demonstrated actions of nicotine or cholinergic agonists
that can be reduced or blocked by a-BTX, which acts selectively at.
neuromuscular nAChRs (Zatz and Brownstein 1981; Farley et al.
1983; de la Garza et al. 1987a).

Radioligand Binding to Putative Nicotine Cholinergic
Receptors in Mammalian Brain

Many receptors for neurotransmitters in the brain have been
identified through the use of radiolabeled probes (radioligands).
Attempts to label putative brain nAChRs have used compounds with
known potency at peripheral sites (see Table 2).

Agonist Binding

The stereospecific, saturable, and reversible binding of 3H-nicotine
to rodent brain is well-described (Roman0 and Goldstein 1980; Marks
and Collins 1982; Costa and Murphy 1983; Benwell and Balfour
1985a; Clarke, Pert, Pert 1984). Most studies have demonstrated the
existence of a population of high-affinity binding sites (reflected by a
dissociation constant in the low nanomolar range) that is potently

89


TABLE 2.-Radioligands for putative nicotinic cholinergic
      receptors in mammals

Antagonists

    Functional
Bmd  antagonism        Sites examned           Agonists

"`[.BTX       Yes     Yes     Muscle endplate            `H-nicotine
           Yes     YE     Autonomic ganglia, spinal cord
           Yes     YCS     Bram cc&am sites only,      JH-methylcarbachol

!"hZlJa tOXln    Yes     ses     Muscle endplate            `H-ACh iwith excess
           Yes     ND1     BLWI              muscarinic antagonist
                                          and AChE inhibitort
`H-dTC        ND     Yes    Muscle. spinal cord, ganglia
           Yes     Yt?S     Brain


`H-DHBE       ND     Yes     Muscle. autonomic ganglia
           Yes     Yes     Dram. spinal cord

Neosurugat0x1n   ND     No     Muscle endplate
           ND     Yes     Autonomic ganglia
           Yes     Yes     Brain lmhlbits `H-nxotinel


' ND-no data

inhibited by nicotinic agonists including ACh. In contrast, most
nicotinic antagonists have very low affinity for this site. Binding
with similar characteristics has been reported in rat brain tissue
with 3H-methyl-carbachol (Abood and Grassi 1986; Boksa and
Quirion 1987) and with 3H-ACh in the presence of excess atropine to
prevent binding to muscarinic receptor sites (Schwartz, McGee,
Kellar 1982).

In the presence of atropine, tritiated nicotine and 3H-ACh proba-
bly bind to the same population of high-affinity sites in rat brain.
Thus, the two radioligands share the same neuroanatomical distribu-
tion of binding (Clarke, Schwartz et al. 1985; Marks et al. 1986;
Martino-Barrows and Kellar 1987). Binding of both ligands is
inhibited with similar potency by a range of nicotinic agents, is up-
regulated by chronic nicotine treatment in vivo, is down-regulated by
chronic treatment with acetylcholinesterase inhibitors, and is dimin-
ished by disulfide reducing agents in vitro (Marks et al. 1986;
Martino-Barrows and Kellar 1987; Schwartz and Kellar 1983).
Although less well studied, it appears that sites labeled by 3H-
methyl-carbachol are the same as those labeled by 3H-ACh and 3H-
nicotine (Abood and Grassi 1986; Boksa and Quirion 1987). High-
affinity nicotine binding sites have been found in brain tissue of mice
(Marks and Collins 1982), rats (Roman0 and Goldstein 1980),
monkeys (Friedman et al. 1985), and humans (Shimohama et al.
1985; Flynn and Mash 1986; Whitehouse et al. 1986).

Some investigators have reported a second class of sites which are
characterized by lower binding affinity and higher capacity for 3H-

90


nicotine. With no demonstrated differential anatomical distribution
or stereoselectivity (Roman0 and Goldstein 1980; Marks and Collins
1982; Benwell and Balfour 1985b), these low-affinity sites are of
questionable pharmacologic significance, but may be the result of
post mortem proteolysis (Lippiello and Fernandes 1986). Careful
analysis of 3H-nicotine binding conducted in the absence of protease
inhibitors has revealed the existence of five affinity sites or states
(Sloan, Todd, Martin 1984). Functional studies (Martin et al. 1986)
suggest that some of these different sites may represent in vivo sites
of action for nicotine, although it is not clear which if any would be
activated by nicotine doses obtained from typical cigarette smoking.

Radioligand Binding

Many receptors of different nicotine binding affinities have been
reported. It is unclear whether these reflect different conformational
states or binding sites of a single type of receptor, distinct receptor
populations, or a single type of high-affinity site which has under-
gone proteolytic degradation. Preliminary evidence supports the
existence of distinct receptor subtypes labeled by agonists. Two
components of high-affinity 3H-nicctine binding, differing in their
affinity for neosurugatoxin, can be distinguished in rat brain. The
relative proportion of these two components differs in different
regions of the rat brain, suggesting that they are physically distinct
receptors (Yamada et al. 1985).

Antagonist Binding

Most studies of nicotine binding in mammalian brain have used
radioiodinated a-BTX (lz51-BTX), which binds with high affinity and
in a saturable manner to sites in mammalian brain (Schmidt, Hunt,
Polz-Tejera 1980; Oswald and Freeman 1981). This binding is
selectively inhibited by nicotinic agents, including nicotine and ACh.
Cobra (naja) alpha-toxin, like a-BTX, is a selective neuromuscular
blocker in the mammal, and appears to label the same sites as a-BTX
in mammalian brain. Binding is potently inhibited by unlabeled a-
BTX and has a regional distribution resembling that of iz51-BTX
binding (Speth et al. 1977). The antagonist dihydro-beta-erythroidine
(DHBE) binds to two sites in rat brain, but the regional distribution
of binding differs from that of lz51-BTX (Williams and Robinson
1984). DHBE acts with similar potency at both types of peripheral
nAChR in vivo. It is not clear whether 3H-d-tubocurarine binding is
selectively inhibited by nicotinic agents. In rat brain, lz51-BTX binds
to a distinct population of sites that are not labeled with high affinity
(nanomolar kD) by tritiated nicotinic agonists. Radioiodinated a-
BTX sites have a different neuroanatomical distribution (Marks and
Collins 1982; Schwartz, McGee, Kellar 1982; Clarke, Schwartz et al.

91


1985) and can be physically separated from tritiated agonist binding
sites by affinity chromatography (Schneider and Betz 1985; Wonna-
cott 1986). This type of study helps to determine the location and
numbers of nicotine binding sites.

Functional Significance of Nicotinic Binding Sites
High-Affinity Agonist Binding Sites

Brain sites which bind 3H-ACh and 3H-nicotine with high affinity
represent nAChRs that respond in some ways like the C6 type of
receptor found in the periphery (Clarke 1987a). Studies using the 2-
DG technique have revealed that the neuroanatomical pattern of
cerebral activation following the systemic administration of nicotine
in rats is strikingly similar to the distribution of high-affinity agonist
binding demonstrated autoradiographically (London et al. 1985;
Grunwald, Schrok, Kuschinsky 1987). Pretreatment with mecamyla-
mine blocks the effects of nicotine on LCGU, suggesting that
putative ganglionic (CG-type) receptors in the brain are associated
with high-affinity agonist binding.

Most of nicotine's actions on central receptors are blocked by the
CG-selective antagonist mecamylamine. The relevant nAChRs are
probably those which are labeled with high affinity by tritiated
agonists. However, the absence of high-affinity agonist binding sites
in PC12 cells (derived from a pheochromocytoma cell line) known to
express CG-type receptors (Kemp and Morley 1986) indicates that
although central and ganglionic nAChRs have pharmacologic simi-
larities, they may not be identical at the molecular level.

High-affinity agonist binding sites are relevant to long-term effects
of human tobacco smoking. Recently, Benwell, Balfour, and Ander-
son (in press) observed that the density of high-affinity 3H-nicotine
binding in post mortem human brain is higher in smokers than in
nonsmokers. The increased density of sites in smokers is consistent
with studies in animals that show that chronic treatment with
nicotine leads to an increased number of nicotinic receptors in the
brain (Schwartz and Kellar 1983; Marks, Burch, Collins 1983b).

Alpha-Bungarotoxin Binding Sites

Although a-BTX does not block nicotinic actions in all areas of the
CNS (Duggan, Hall, Lee 1976; Egan and North 1986), there are
several reports of antagonism (Zatz and Brownstein 1981; Farley et
al. 1983; de la Garza et al. 1987a). In the rat cerebellum, locally
applied nicotine alters single-unit activity in a manner dependent on
cell type: nicotine excites interneurons but inhibits Purkinje cells.
Both actions are directly postsynaptic (de la Garza et al. 1987, in
press(b)). The inhibitory effects of nicotine are blocked by hexame-


thonium but not by a-BTX, which does block the excitatory effects
(de la Garza et al., in press(a)).

Strain differences exist in mice in the physiological and behavioral
effects of nicotine, in the development of tolerance to these effects,
and in the regional distribution of lz51-BTX binding density (Marks,
Burch, Collins 1983a; Marks, Stitzel, Collins 19861. The genetically
determined variation in response is not readily explained by
differences in brain nicotinic receptors. However, a classical genetic
analysis indicates that the density of `""I-BTX binding sites in mouse
hippocampus correlates with susceptibility to seizures induced by
high doses of nicotine (Miner, Marks, Collins 1984). These and other
considerations (Clarke 1987a) suggest that lZ51-BTX may label a
subtype of nAChR in the brain and that this receptor is pharmaco-
logically akin to the nAChR found in muscle.

Although ""I-BTX binding sites are found in human brain, the
available evidence suggests that nicotine at doses obtained from
cigarette smoking does not activate this population of brain nAChRs.
Rather, the pattern of neuronal activation that follows the in vivo
administration of nicotine in animal experiments, even in doses far
greater than those likely to occur during smoking, resembles the
neuroanatomical distribution of high-affinity agonist binding sites
(London et al. 1985; Grunwald, Schrok, Kuschinsky 1987). However,
this issue is not conclusively resolved, and a potential role for
bungarotoxin binding receptors in mediating effects of smoking
cannot be completely excluded.

Behavioral and Physiological Studies

The effects of mecamylamine on several responses elicited by
nicotine in mice have been examined (Collins et al. 1986). The
responses are of two major classes: those blocked by low doses of
mecamylamine (inhibitory concentrations for 50 percent of mice
tested (IC,,) <O.l mg/kg) (seizures and startle response) and those
blocked by higher doses UC,,, approximately 1 mg/kg) (effects on
respiratory, heart rate, body temperature, and Y-maze activity).
Strain differences are also apparent in the sensitivity to mecamyla-
mine blockade. These findings are consistent with the existence of at
least two types of central nAChR.

The Neuroanatomical Distribution of Nicotinic Binding
Sites in the Brain

High-Affinity Agonist Binding Sites
Rodent

Autoradiographic maps of high-affinity nicotinic binding sites in
rat brain are essentially identical for 3H-nicotine, 3H-ACh, and 3H-
methyl-carbachol (Clarke, Pert, Pert 1984; Clarke, Schwartz et al.

93


1985; London, Waller, Wamsley 1985; Boksa and Quirion 1987).
Dense labeling is observed (11 in the medial habenula and interpe-
duncular nucleus, which appear to belong to a common cholinergic
system; (21 in the so-called specific motor and sensory nuclei of the
thalamus and in layers III and IV of cerebral cortex with which they
communicate; (3) in the substantia nigra pars compacta and ventral
tegmental area, where labeling is associated with dopaminergic cell
bodies (Clarke and Pert 1985); and (4) in the molecular layer of the
dentate gyrus, the presubiculum, and the superficial layers of the
superior colliculus. Labeling is sparse in the hippocampus and
hypothalamus.

Monkey

The autoradiographic distribution of high-affinity 3H-nicotine
binding in rhesus monkey brain is similar to that in the rat
(Friedman et al. 1985). Dense labeling has been noted in the anterior
thalamic nuclei and in a band within cerebral cortex layer III. The
latter band is densest and widest in the primary sensory areas.
Several other thalamic nuclei are moderately labeled, but as in the
rat, the label is sparse in the midline thalamic nuclei. In contrast to
findings for the rat, the medial habenula appears unlabeled.

Human

High-affinity agonist binding has not been mapped autoradio-
graphically in human brain. However, assays of a few dissected brain
areas suggest the following pattern: nucleus basalis of Meynert >
thalamus > putamen > hippocampus, cerebellum, cerebral cortex,
and caudate nucleus (Shimohama et al. 19851. Two affinity sites for
3H-nicotine have been detected, and the regional distribution
observed reflects the presence of both sites.

Alpha-Bungarotoxin Binding Sites

Because "j1-BTX sites may not be relevant to tobacco smoking,
they will be discussed only briefly here. There are clear differences of
regional distribution not only between mice and rats, but also
between different strains of mice (Marks et al. 19861. The autoradio-
graphic distribution of lz51-BTX labeling in rat brain is strikingly
different from the pattern of 3H-agonist labeling, with highest site
density in hippocampus, hypothalamus, and superior and inferior
colliculi (Clarke, Schwartz et al. 1985). An attempt to map lz51-BTX
binding in human brain was hampered by a high degree of
nonspecific binding, with diffuse specific labeling in the hippocam-
pus and cerebral cortex (Lang and Henke 19831.

94


Molecular Biology

Goldman and colleagues have mapped regions in the brain which
contain cell bodies expressing RNA that codes for putative nAChRs.
The RN.4 identified is homologous to cDNA clones encoding the
alpha subunits of the muscle nAChR and a putative neuronal
nAChR (Goldman et al. 1986; Goldman et al. 1987). These and
related findings show that a family of genes exists that codes for
proteins similar to, but not identical with, the muscle nAChR. The
functional role of these putative nAChR subtypes in the CNS is not
clear.

Central Nicotinic Cholinergic Receptors: Pre- or
Postsynaptic?

Presynaptic Regulation of Neurotransmitter Release

The release of ACh from some nerve terminals in the CNS (Rowe11
and Winkler 1984; Beani et al. 1985) and periphery (Briggs and
Cooper 1982) is increased by activation of presynaptic nicotinic
"autoreceptors." Preliminary evidence from lesion experiments
suggests that some nicotinic autoreceptors in the brain may be high-
affinity 3H-nicotine binding sites (Clarke et al. 1986).

Nicotine also modulates the release of certain other neurotrans-
mitters by acting at receptors located on nerve terminals. This form
of regulation has been shown for dopaminergic, noradrenergic, and
serotonergic terminals (Starke 1977; Chesselet 1984). Lesion studies
suggest that these receptors are labeled by 3H-agonists (Schwartz,
Lehmann, Kellar 1984; Clarke and Pert 1985; Prutsky, Shaw,
Cynader 1987).

Somatodendritic Postsynaptic Actions

Much of 3H-agonist labeling probably represents nAChRs located
on neuronal cell bodies or dendrites. For example, nicotine excites
neurons postsynaptically in the medial habenula, locus coeruleus,
and interpeduncular nucleus, all areas of moderate to dense 3H-
agonist binding (Brown, Docherty, Halliwell 1983; Egan and North
1986; McCormick and Prince 19871.

Neuroendocrine and Endocrine Effects of Nicotine

Nicotine has direct and indirect effects on several neuroendocrine
and endocrine systems (Balfour 1982; Clarke 1987a; Hall 1982). This
Section reviews research on the effects of nicotine in animals and
humans that are relevant to understanding cigarette smoking.
Nicotine effects on cholinergic and noncholinergic nicotinic recep-
tors, as well as on the release of catecholamines, monoamines,
pituitary hormones, cortisol, and other neuroendocrine chemicals,

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are discussed. Effects on single neuroregulators are emphasized, but
it is important to recognize that there are extensive interrelation-
ships among these substances (Tuomisto and Mtinnisto 1985).

Nicotine has effects on peripheral endocrine as well as on central
neuroendocrine functions. In the early 1900s researchers discovered
that nicotine stimulated autonomic ganglia (ganglia were painted
with tobacco solutions), inducing such effects as the release of
adrenal catecholamines (Larson, Haag, Silvette 1961). As the health
consequences of cigarette smoking have become clearer, many
investigators have sought to determine tobacco's effects on the
endocrine system, with the possibility that understanding such
effects may help to explain smoking behavior. Nicotine is regarded
as the major pharmacologic agent in tobacco and tobacco smoke
responsible for alterations in endocrine function. However, there has
not been a systematic evaluation of the effects of metabolites of
nicotine or constituents of tobacco other than nicotine on the
endocrine system.

The functional significance of nicotine-induced perturbations in
hormonal patterns and the role of neuroregulators in smoking are
poorly understood. Extensive literature using nicotinic agonists and
antagonists indicates relationships between cholinergic activity and
particular behavioral effects (Henningfield et al. 1983; Kumar,
Reavill, Stolerman, in press). Similar strategies have been employed
to explore the contributions of catecholamines to smoking-related
behavior. However, the exploration of the importance of neuroregu-
lators in the reinforcement of cigarette smoking is still at an early
stage.

Cholinergic Effects

Nicotine has cholinergic effects in the PNS and CNS. Nicotine is a
cholinergic agonist. at peripheral autonomic ganglia and somatic
neuromuscular junctions at low doses and becomes an antagonist at
high doses (Voile and Koelle 1975). Nicotine also releases ACh in the
cerebral cortex (Armitage, Hall, Morrison 1968; Rowe11 and Winkler
1984) and in the myenteric plexus of the peripheral ANS (Briggs and
Cooper 1982). Balfour (1982) has suggested that cortical arousal (see
Electrophysiological Actions of Nicotine for a detailed discussion) is
mediated by ACh release but that behavioral stimulation (see
Chapter IV) either is not mediated by ACh release or does not
depend on the action of ACh at a muscarinic receptor.

Studies involving intracerebral administration of nicotine have
been used to determine the loci of nicotine's action (Kammerling et
al. 1982; Wu and Martin 1983). The injection of nicotine into the
cerebral ventricles of cats, dogs, and rats produces a variety of effects
including changes in cardiovascular activity, body temperature,
respiration, salivation, muscle reflex tone, and electrocortical indices

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of sleep and arousal; the direction and duration of effects depend on
dosage and on baseline response parameters (Ha!1 1982).

Nicotine's cholinergic actions can affect other neuroregulators in
the body (Andersson 1985). Nicotine stimulates NE release in the
hypot,halamus by a Ca'- -dependent process that can be inhibited by
prior administration of hexamethonium or ACh (Hall and Turner
1972; Westfail 1974). The mechanism resembles nicotine's effects on
peripheral adrenergic nerve terminals (Westfall and Brasted 1972).
At high dose levels. nicotine stimulates NE release by displacing it
from vesicle stores at sites outside the hypothalamus (Balfour 1982).
These actions are relevant to understanding the reinforcing effects
of nicotine. For example, using drug discrimination procedures,
Rosecrans (1.987) has demonstrated that intact central NE and
dopamine IDA) function were required to elicit the cue properties of
nicotine.

Intravenous administration of nicotine modulates the release of
both neurohypophyseal and adenohypophyseal hormones (Bisset et
al. 1975; Hall, Francis, Morrison 1978). Hillhouse, Burden, and Jones
(1975) found that the in vitro application of ACh to the hypophysio-
tropic area of the rat caused a significant increase in the basal
secretion of corticotropin-releasing hormone (as measured by bioas-
say), which in t,urn controls, via the anterior pituitary, the release of
the pro-opiomelanocortin (POMC) group of hormones-+-endorphin,
@lipotropin, melanocyte-stimulating hormone-releasing factor, and
adrenocorticotropic hormone (ACTH) (Meites and Sonntag 1981).
The humoral mechanism for the release of vasopressin has been
traced from the medulla to the paraventricular nuclei of the
hypothalamus (Bisset et al. 1975; Castro de Souza and Rocha e Silva
1977). Similarly, Risch and colleagues (1980) have demonstrated a
cholinergic mechanism for the release of 8-endorphin.

Modulation of Catecholamine and Serotonin Activity

Dale and Laidlaw (1912) found that the pressor response of the cat
to nicot,ine was due in part to the release of epinephrine from the
adrenal glands. Over the past 75 years, a large body of research has
confirmed and further investigated this phenomenon. Stewart and
Rogoff (1919) quantified the effect of nicotine on adrenal epinephrine
release. Kottegoda (1953) observed that nicotine releases catechol-
amines from extra-adrenal chromaffin tissues. Watt,s (1961) demon-
strated the effect of smoking on adrenal secretion of epinephrine.
Hill and Wynder (1974) reported that increasing the nicotine content
in cigarette smoke progressively increased the serum concentration
of epinephrine, but not NE. Winternitz and Quillen (1977) found that
the excretion of urinary catecholamines tended to be higher on
smoking days than on nonsmoking days. Several recent studies have
focused on the role of nicotine and the mechanisms involved in the

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release of catecholamines from cultured chromaffin cells (Forsberg,
Rojas. Pollard 1986). Earlier experiments by Douglas and Rubin
[1961), using denervated perfused cat adrenal glands, indicated that
nicotine augments catecholamine release from chromaffin cells by
promoting an influx of extracellular calcium. Forsberg, Rojas, and
Pollard (1986) suggested that nicotine-induced catecholamine secre-
tion may be mediated by phosphoinositide metabolism in bovine
adrenal chromaffin cells.

The anatomical localization and importance of biogenic mono-
amines such as serotonin (5-HT [5-hydroxytryptamine]), DA, and NE
have been the subject of intense research for the past 30 years. The
classic studies of Dahlstrom and Fuxe (1966) revealed that neurons
containing these amines were localized in specific ascending projec-
tion systems; descending monoaminergic neurons have also been
described. The physiological integrity of these systems was further
demonstrated by Aghajanian, Rosecrans, and Sheard (1967J who
observed that stimulation of 5-HT cell bodies localized in the
midbrain raphe nucleus released 5-HT from nerve endings located in
the more rostra1 forebrain. The recognition that these amine systems
constitute a unique interneuronal communication system has played
a central role in understanding underlying neurochemical and
behavioral mechanisms.

The cholinergic system has undergone a similar analysis (Fibiger
1982), but the delineation of specific cholinergic pathways has been
more difficult because no histochemical method has been available
for ACh. It does appear, however, that the cholinergic system is
similarly organized and interacts with specific biogenic amine
pathways. For example, Robinson (1983) has clearly shown that both
5-HT and DA systems exert tonic inhibitory control over ACh
turnover in both the hippocampus and frontal cortex regions.
Lesions of the medial raphe nuclei increase the ACh turnover rate in
hippocampal sites, while lesions of the dorsal raphe elicit a similar
effect in frontal cortical areas. Evidence of DA control comes from
the observation that the catecholamine neurotoxin, 6-OHDA, when
injected into the DA-rich septal area, facilitated hippocampal ACh
turnover. The research of Kellar, Schwartz. and Martin0 (1987) and
others also suggests that nicotinic receptors may occupy a presynap-
tic site on select DA and 5-HT nerve endings. Westfall, Grant, and
Perry (1983), using a tissue slice preparation, have shown that the
DMPP-induced stimulation of nicotinic receptors in the striatum will
facilitate the release of both 5-HT and DA. This preparation is devoid
of cell bodies or 5-HT- and DA-containing axon terminals, suggesting
that these nicotinic cholinergic receptors are primarily presynaptic.
Further, hexamethonium, but not atropine, attenuated nicotine-
induced amine release, confirming that these effects are nicotinic in
nature.

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Nicotine may have simultaneous actions on many types of
neurons. Even though only one kind of receptor may be stimulated,
either activation or inhibition of a particular SIIT, NE, or DA
neuron may be the ultimate outcome. Conversely, the activity of
specific cholinergic neurons may also be controlled by one of these
biogenic-amine-containing projection systems. Nicotine appears to
produce its discriminative stimulus effect in at least one major brain
area, the hippocampus. This site is rendered insensitive if DA
neurons innervating this area are destroyed (Rosecrans 1987). The
interrelationships of these amine pathways are important to under-
stand nicotine's effects on behavior and its effects on the neuroendoc-
rine system because of the central role that these amine systems
play in the hypothalamic control of the pituitary.

Effects on Serotonergic Neurons

Research evaluating the relationship between nicotine and 5-HT
has involved several different approaches. Hendry and Rosecrans
(1982) compared the effects of nicotine on conditioned and uncondi-
tioned behaviors in rats selected for differences in physical activity
and 5-HT turnover. Balfour, Khuller, and Longden (1975) observed
that acute doses of nicotine were capable of attenuating hippocampal
5-HT turnover, an effect specific to the hippocampus. Fuxe and
colleagues (19871 did not observe any acute changes in 5-HT function
following acute nicotine dosing but did observe a significant reduc-
tion of 5-HT turnover following repeated doses (3 x 2 mg/kg/hr). This
effect, however, was suggested to be due to cotinine, the primary
metabolite of nicotine.

In addition to attempts to correlate 5-HT function with some
pharmacologic effect of nicotine, investigators have evaluated poten-
tial links between 5-HT and neuroendocrine function. Balfour,
Khuller, and Longden (1975) showed a relationship between 5-HT
and nicotine's ability to induce the release of plasma corticosterone,
presumably by activation of the pituitary-adrenal axis. Following
acute nicotine injections in the rat, a reduction in 5-HT turnover
correlated with an increase in plasma corticosterone. Rats exhibited
tolerance to pituitary activation following repeated nicot.ine doses,
but not to the attenuation of hippocampal 5-HT turnover. Stress
antagonized nicotine-induced reductions of hippocampal 5-HT. Also,
nicotine was reported to inhibit the adaptive response to adrenocorti-
cal stimulation following chronic stress (Balfour, Graham, Vale
1986). One interpretation of these data is that nicotine can modify
how rats adapt to stress, which may be mediated by changes in
hippocampal 5-HT function. At this point, however, it is difficult to
draw firm conclusions concerning how nicotine affects 5-HT neurons
and whether this neurotransmitter is involved in any of nicotine's

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effects on neuroendocrine function. Hippocampal 5-HT turnover
appears to be selectively attenuated by nicotine.

Effects on Catecholaminergic Neurons

Studies of the effects of nicotine on NE-containing neurons have
produced mixed results. Earlier work suggested that nicotine may
affect behavior via a NE component, but recent research has not
supported such claims (Balfour 1982). It has been reported that
nicotine releases DA from brain tissue (Westfall, Grant, Perry 1983).
Lichtenst,eiger and colleagues (1982) observed that nicotine releases
DA through an acceleration of the firing rate of DA cell bodies
located in substantia nigra zona compacta when nicotine is adminis-
tered via iontophoretic application or S.C. (0.4 to 1.0 mg/kg). This
activation was marked by a significant increase in striatal DA
turnover; DHBE, but not atropine, attenuated nigrostriatal activa-
tion. Evidence that nicotine facilitates the firing of DA cell bodies by
stimulating nicotinic cholinergic receptors has recently been report-
ed by Clarke, Hommer, and coworkers (1985), who showed a specific
effect of nicotine antagonized by mecamylamine on pars compacta
cell bodies. Connelly and Littleton (1983) noted t.hat DA release from
synaptosomes lacked stereoselectivity but was blocked by the
ganglionic-blocking drug pempidine.

Fuxe and coworkers (1986, 1987) have studied nicotine's effects on
central catecholamine neurons in relation to neuroendocrine func-
tion. These investigators use quantitative histofluorometric tech-
niques that measure the disappearance of catecholamine stores by
administering a tyrosine hydroxylase inhibitor (AMPT) to rats
receiving various doses of nicotine or exposed to tobacco smoke.
Tissues are then exposed to formaldehyde gas, and histofluorescence
in AMPT-treated rats is evaluated in comparison to controls.

Nicotine is a potent activator of both DA and NE neuron systems
located primarily in the median eminence and in areas of the
hypothalamus. These effects result from a stimulation of nicotinic
cholinergic receptors, generally antagonized by mecamylamine.
Intermittent nicotine dosing (4 x 2 mg/kg, S.C. every 30 min) or
tobacco smoke exposure (rats were exposed to one to four cigarettes
with a smoking machine-determined nicotine yield of 2.6 mg; rats
received 8 puffs at lo-min intervals) results in a decrease of
prolactin, thyroid-stimulating hormone (TSH), and luteinizing hor-
mone (LH) and an increase of plasma corticosterone levels. Nicotine
doses of 0.3 mg/kg administered iv. induce an overall activation of
the hypothalamic-pituitary axis, causing an increase of both ACTH
and prolactin that subsides within 60 min. Tolerance to the
corticosterone response develops after repeated nicotine doses, and
there is evidence that it develops after a single dose of nicotine
(Sharp and Beyer 1986; Sharp et al. 1987). Restraint stress increases

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ACTH, corticosterone, and prolactin levels and decreases DA and NE
levels in hypothalamic regions. This stressor attenuates nicotine's
activation of NE neurons but does not reverse its attenuating effects
on prolactin.

Nicotine appears to be associated with neuroendocrine activity by
NE and DA activation (Fuxe et al. 1987). Immunohistochemical
studies suggest that alterations in NE function are more important
for the control of the pituitary-adrenal-axis, while DA turnover
appears to be crucial for nicotine's effects on prolactin, LH, and
follicle-stimulating hormone (FSH). Moreover, these studies indicate
that similar nAChRs are located within both DA mesolimbic and
neostriatal systems.

Stimulation of Pituitary Hormones

Nicotine administration and cigarette smoking stimulate the
release of several anterior and posterior pituitary hormones. Seyler
and coworkers (1986) had human subjects smoke two high-nicotine
(2.87 mg) cigarettes in quick succession. Plasma levels of prolactin,
ACTH, l3-endorphin/P-lipoprotein, growth hormone (GH), vasopres-
sin, and neurophysin I increased. No change was seen in TSH, LH, or
FSH. The rapid smoking paradigm used by Seyler and coworkers
(1986) may have contributed to the effects of nicotine. Growth
hormone levels exhibited a prolonged increase after subjects smoked
three cigarettes in rapid succession (Sandberg et al. 1973). In
experiments conducted by Winternitz and Quillen (1977) with male
habitual smokers, GH began to rise after two cigarettes, peaked at 1
hr, and then returned to control levels while smoking continued.
Wilkins and colleagues (1982) also found that smoking increases GH
levels and presented evidence that the effect is nicotine mediated.
Coiro and coworkers (1984) reported that the increase in GH
produced by clonidine was greatly enhanced by cigarette smoking,
suggesting that nicotinic cholinergic and adrenergic mechanisms
might interact in the stimulation of GH secretion.

The TSH plasma levels were not affected when nicotine was
administered over a 60-min period to female rats (Blake 1974). In
studies involving exposure to cigarette smoke, Andersen and col-
leagues (1982) reported a lowering of TSH secretion in rats, but as
noted, Seyler and coworkers (1986) found no change in human
subjects. Thus, the data on the effects of nicotine on TSH release are
inconclusive at this time.

ACTH plasma levels increased after i.p. injection of nicotine in the
rat (Conte-Devolx et al. 1981). In similar experiments, Cam and
Bassett (1983b) found that elevated ACTH levels peaked and rapidly
declined to a sustained plateau level. Sharp and Beyer (1986)
reported that the effects of nicotine on ACTH in rats show a rapid
and marked desensitization. Seyler and coworkers (1984) had male

101


subjects smoke cigarettes containing 0.48 or 2.87 mg of nicotine. No
increases in ACTH or cortisol were detected after subjects smoked
0.48-mg-nicotine cigarettes. Cortisol levels rose significantly in 11 of
15 instances after smoking the high-nicotine cigarettes, but ACTH
rose in only 5 of the 11 instances when cortisol increased. Each
ACTH increase occurred in a subject who reported nausea and was
observed to be pale, sweaty, and tachycardic. Seyler and coworkers
(1984) studied smokers and concluded that ACTH release occurs only
in smokers who become nauseated.

LH levels were reduced in male rats exposed to unfiltered
cigarette smoke, while FSH was unchanged (Andersen et al. 1982). In
experiments by Winternitz and Quillen (1977), there were no
differences in LH and FSH among male cigarette smokers while
smoking as compared with not smoking. Seyler and colleagues (1986)
found no change in human LH or FSH levels after smoking. There is
no evidence of gonadotropin release stimulated by nicotine or
smoking.

Prolactin plasma levels were lowered considerably in lactating
rats injected twice daily with nicotine (Terkel et al. 1973). It was
suggested that failure of prolactin release following chronic nicotine
administration was responsible for low milk production and starva-
tion of pups. Blake and Sawyer (1972) found that, in lactating rats,
the rapid suckling-induced release of prolactin into the blood is
inhibited by S.C. injections of nicotine. Ferry, McLean, and Nikitito-
vich-Winer (1974) reported that tobacco smoke inhalation in rats
delays the suckling-induced release of prolactin. Andersen and
coworkers (1982) found that prolactin secretion was reduced in male
rats in a dose-dependent manner by exposure to unfiltered cigarette
smoke. However, Sharp and Beyer (1986) reported that the effects of
nicotine on prolactin in rats shows a biphasic effect, first increasing
and then decreasing. Suppressed prolactin levels were found in
female smokers who were breast feeding (Andersen et al. 1982).
These researchers noted that smokers weaned their babies signifi-
cantly earlier than nonsmokers. However, Wilkins and coworkers
(1982) observed an increased level of prolactin in male chronic
smokers.

Arginim Va.sopressin

In addition t.o its antidiuretic effects, arginine vasopressin acts as a
vasoconstrictor (Munck, Guyre, Holbrook 1984; Waeber et al. 1984).
Arginine vasopressin may also act as a neuromodulator in pathways
that affect behavior. It has been shown to promote memory
consolidation and retrieval in rats (Bohus, Kovacs, de Wied 1978) and
there are reports of memory enhancement following intranasal
administration of a vasopressin analog in both normal and memory-
deficient humans (LeBoeuf, Lodge, Eames 1978; Legros et al. 1978;

102


Weingartner et al. 1981). Nicotinic cholinergic receptors in the
medial basal hypothalamus and muscerinic cholinergic receptors in
the neurohypophysis (posterior pituitary) have been implicated in
the release of vasopressin (Gregg 19851. Nicotine has been found to
stimulate vasopressin release in a dose-related manner in animals
(Reaves et al. 1981; Siegel et al. 1983) and in humans (Dietz et al.
1984; Pomerleau et al. 1983; Seyler et al. 1986). These observations
are consistent, with the effects of nicotine on cognitive performance
(Chapter VI).

The Pro-Opiomelanocorticotropin Group of Hormones

The POMC hormones are released in response to stress and in
response to corticotropin-releasing hormone (Munck, Guyre, Hol-
brook 1984; Krieger and Martin 19811. ACTH has behavioral effects
and stimulates the release of steroids such as cortisol from the
adrenal cortex. ACTH produces rapid cycling between sleeping and
waking as well as sexual stimulation, grooming/scratching, blocking
of opiate effects such as analgesia, and the enhancement of attention
and stimulus discrimination (Bertolini and Gessa 1981). Endogenous
opioids, such as 8-endorphin, potentiate vagal reflexes, cause respira-
tory depression, lower blood pressure, block the release of catechol-
amines (Beaumont and Hughes 1979; Schwartz 19811, have antinoci-
ceptive effects (van Ree and de Wied 19811, and modulate neuro-
transmitter systems leading to amnesic effects (Izquierdo et al. 1980;
Introini and Baratti 19841. It has been suggested that the primary
function of the endogenous opioids is metabolic, serving to conserve
body resources and energy (Amir, Brown, Amit 1980; Margules 1979;
Millan and Emrich 1981).

Nicotine appears to stimulate the release of corticotropin-releasing
hormone from the hypothalamus through a nicotinic cholinergic
mechanism (Hillhouse, Burden, Jones 1975; Weidenfeld et al. 1983).
Using an isolated perfused mouse brain preparation, Marty and
coworkers (1985) demonstrated that nicotine stimulates secretion of
8-endorphin and ACTH in a dose-related manner when applied
directly to the hypothalamus but not when applied to t,he pituitary.
The work of Sharp and Beyer (19861 supports this finding; they
reported that the secretion of ACTH following nicotine was unaffect-
ed by adrenalectomy. Nicotine administration to rats has also been
shown to increase the plasma levels of corticosterone, ACTH, and /3-
endorphin in a dose-related manner (Conte-Devolx et al. 1981).
Termination of chronic nicotine administration reduced hypotha-
lamic 8-endorphin levels (Rosecrans, Hendry, Hong 1985). Hurlick
and Corrigal (1987) have also observed that the narcotic antagonist
naltrexone inhibits some nicotine-modulated behavior in mice,
providing a possible link between nicotine stimulation of endogenous
opioid activity and behavioral responses. Acute administration of

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nicotine increases levels of plasma ACTH and corticosterone sharply
(Cam and Bassett 1983b), while chronic exposure results in complete
adaptation (Cam and Bassett 1984). Melanocyte-stimulating hor-
mone was decreased and &endorphin was increased by i.p. injections
of nicotine in the rat (~Conte-Devolx et al. 1981).

Risch and colleagues (1980. 198211 have accumulated evidence for
cholinergic control of cortisol, prolactin, and 8-endorphin release in
humans. Rapid smoking increases circulating cortisol, 8-endorphin,
and neurophysin I !Pomerleau et al. 1983; Seyler et al. 1984; Novack
and Allen-Rowlands 1985; Novack, Allen-Rowlands, Gann, in press).
Moreover, in a study that examined the role of endogenous opioid
mechanisms in smoking, Tobin, Jenouri, and Sackner (1982) ob-
served that mean inspiratory flow rate increases during the smoking
of a cigarette but is depressed shortly after smoking. Naloxone had
no effect on the initial stimulation of respiration in response to
smoking but did significantly blunt the subsequent depression of
respiration. The significance of these findings for the control of
cigarette smoking remains equivocal (Karras and Kane 1980;
Nemeth-Coslett and Griffiths 1986; Chapter IV).

Thyroid

Most of the earlier work (1930s through 1950s) assessing the
effects of nicotine on thyroid function involved histological studies of
the thyroid glands from animals treated chronically with nicotine.
The findings are inconsistent in that some studies suggest elevated
thyroid activity and others do not (Cam and Bassett 1983a). In a
more recent study of nicotine's action on the plasma levels of the
thyroid hormones, thyroxine (T4) and triiodothyronine (T31, Cam
and Bassett (1983a) found that a single i.p. injection of 200 pg/kg did
not alter the level of either hormone, although it did produce an
increase in plasma corticosterone. As mentioned earlier, nicotine
does not consistently affect TSH in animals or humans (Blake 1974;
Seyler et al. 19861.

Adrenal Cortex

Several studies in animals and human subject.s have reported that
nicotine and cigarette smoking lead to elevated levels of corticoste-
roids. Kershbaum and colleagues (1968) administered nicotine i.v. to
anesthetized dogs and found a 64 percent rise in plasma corticoste-
roids. In rat,s. corticosteroid concentrations increased 50 percent
after i.p. administration of nicotine. Suzuki and coworkers (19731
also reported adrenal cortical secretion in response to nicotine in
conscious and anesthetized dogs. The effects of nicotine on plasma
corticosteroids in stressed and unstressed rats were studied by
Balfour, Khuller, and Longden (1975). The administration of nicotine
to unstressed rats caused a rise in corticosterone which persisted for

104


60 min. Nicotine did not affect plasma corticosterone concentration
in rats stressed by being placed on an elevated platform. Ot.her
studies showed increased plasma corticosteroid levels after nicotine
administration (Turner 1975; Cam, Bassett, Cairncross 1979; Cam
and Bassett 1983b). Andersen and colleagues (1982) exposed male
rats to unfiltered cigarette smoke and found a dose-related increase
in corticosterone secretion. Filtered cigarette smoke was inactive.

Seifert and coworkers (i984) found that the chronic administration
of 0.5 or 1.0 mg/kg of nicotine S.C. twice daily for 8 weeks to rats
produced a marked decrease in plasma aldosterone levels. In this
study, nicotine had no effect on plasma corticosterone concentration.

Hokfelt (1961) report,ed increases in plasma cortisol and urinary
17-hydroxycorticosteroids following cigarette smoking in human
subjects. Kershbaum and coworkers (1968) reported similar results
involving elevations of 11-hydroxycorticosteroids. Hill and Wynder
(1974) found that serum corticosteroids were markedly elevated after
high-nicotine (2.73 mg) cigarettes were smoked. No increase was seen
with cigarettes containing less nicotine. Cryer and colleagues (1976)
also found an increase in circulating levels of corticosteroids after
smoking. Winternitz and Quillen (1977) reported a sharp increase in
circulating cortisol after two cigarettes. The levels were maintained
through the smoking period and fell gradually to normal. Wilkins
and coworkers (1982) also observed increased levels of cortisol after
2-mg-nicotine cigarettes were smoked. No increases in cortisol were
detected after smoking 0.48-mg-nicotine cigarettes, but cortisol rose
significantly in 11 of 15 cases smoking 2.87-mg-nicotine cigarettes
(Seyler et al. 1984). Consistent with these results is the observation of
Puddey and colleagues (1984) that cessation of smoking is associated
with a significant fall in cortisol levels.

In contrast to these findings, Tucci and Sode (1972) reported intact
diurnal circadian variations of cortisol and unchanged 24-hr 17-
hydroxycorticosteroids durin, u smoking. Benowitz, Kuyt, and Jacob
(1984) studied 10 subjects who either smoked their usual brand of
cigarettes, some of which contained 2.5 mg nicotine, or abstained.
Plasma cortisol concentrations throughout the day did not differ
during smoking or abstaining. Thus, while the majority of human
and animal data indicates that nicotine or smoking elevates cortico-
steroid levels, the effects appear to be influenced by dose, time, and
perhaps other factors.

Many investigators cited above have proposed that nicotine's
effects on corticosteroids are mediated by the release of ACTH.
Indeed, hypophysecbomy abolished the increase in adrenocortical
secretion following nicotine administration (Suzuki et al. 1973; Cam,
Bassett, Cairncross 1979) and nicotine-induced increase in plasma
ACTH precedes the increase in cortisol (Conte-Devolx et al. 1981).
However, Turner (1975) found that bilateral adrenal demedullation

105


abolished the rise in corticosterone in response to nicotine and
suggested that the effect of nicotine is mediated via adrenal release
of catecholamines and that centrally mediated stimulation is not
significant. In contrast, the work of Matta and associates (1987)
demonstrates that the effects of nicotine on ACTH secretion are
centrally mediated. Rubin and Warner (1975) have also shown that
nicotine directly stimulates isolated adrenocortical cells of the cat.
The stimulant effect was dose-dependent and required the presence
of calcium. These experiments also indicated that nicotine enhances
the steroidogenic effect of ACTH.

Androgens

In male beagles, chronic smoking of high-nicotine/tar cigarettes
was associated with decreased activity of 7a-hydroxylase active on
testosterone (Mittler, Pogach, Ertel 1983). Testicular 66- and 16a-
hydroxylases were not altered, while the hepatic androgen 6(3-
hydroxylase activity in the testis was stimulated markedly by
smoking. Serum testosterone levels were reduced to 54 percent of
control levels by heavy smoking. It was concluded that chronic
cigarette smoking increased hepatic metabolism of testosterone,
resulting in lowered serum testosterone levels. However, it may be
that total testosterone is lower while free testosterone is not.

Estrogens

Cigarette smoking is associated with antiestrogenic effects in
women, including earlier menopause, lower incidence of breast and
endometrial cancer, and increased osteoporosis. MacMahon and
colleagues 11982) reported lower urinary estrogen levels in premeno-
pausal smokers than in premenopausal nonsmokers and suggested
that the low estrogen secretion reflected lower estrogen production,
based on decreased estrone, estradiol, and estriol. However, 2-
hydroxyestrogens, the major metabolites of estradiol in women, were
not measured. Jensen, Christiansen, and Rodbro (1985) presented
evidence for increased hepatic metabolism of estrogens as a result of
smoking based on an observation of decreased serum estrogen levels
in postmenopausal smokers receiving exogenous hormone therapy.
This study examined 136 women treated for 1 year with different
doses of estrogen. Reduction of serum estrogen was most pronounced
in the highest estrogen-dose group. There was a significant inverse
correlation between the number of cigarettes smoked daily and
changes in serum estrogen. Michnovicz and colleagues (1986) found a
significant increase in estradiol 2-hydroxylation in premenopausal
women who smoked at least 15 cigarettes/day. They concluded that
smoking exerts a powerful inducing effect on the 2-hydroxylation
pathway of estradiol metabolism, which is likely to lead to decreased
bioavailability of hormone at estrogen target tissues.

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Pancreas and Carbohydrate Metabolism

The body weight of smokers is consistently lower than that of
nonsmokers, and smokers tend to gain weight after cessation of
smoking (see Chapter VI for a detailed discussion of these relation-
ships). These phenomena are thought to contribute to tobacco use.
Glauser and coworkers (1970) and Hofstetter and coworkers (1986)
suggested that a change in metabolic rate is partially responsible for
these effects. Schechter and Cook (1976) and Grunberg, Bowen, and
Morse (1984) showed that rats which were administered nicotine lost
body weight without reducing food intake, although the body weight
changes were not as great as when eating behavior declined as well
(Grunberg 1982). Grunberg (1986) has pointed out that differences in
body weight between smokers and nonsmokers result from changes
in energy consumption (via changes in specific food consumption)
and changes in energy utilization. Recently, Grunberg and cowork-
ers (1988) have reported reductions of insulin levels accompanying
nicotine administration in rats which could result in an increase in
the utilization of fat, protein, and glycogen. This finding is consistent
with work of Tjalve and Popov (1973), using rabbit pancreas pieces,
and studies by Florey, Milner, and Miall (1977) of human smokers
versus nonsmokers. Grunberg and coworkers (1988) have suggested
that the effects of nicotine on insulin levels also may be involved in
the nicotine-induced decrease of sweet food preferences.

Electrophysiological Actions of Nicotine
Electrocortical Effects

The brain responds to electrical as well as to chemical stimuli.
Therefore, measurements of the electrophysiological actions of
nicotine complement studies of its chemical effects. In addition,
electrophysiological activity reflects function that may relate to
sensory and cognitive changes observed in humans after smoking
(see Chapter VI). In animals, nicotine produces changes ranging
from subtle latency decreases in the primary auditory pathway to
seizures. The electrophysiological actions of nicotine may help to
relate the anatomical and receptor data (discussed earlier in this
Chapter) with sensory and cognitive data (discussed in greater detail
in Chapter VI).

The human studies on electrocortical effects of nicotine have some
methodological limitations. Most of the human studies had subjects
smoke cigarettes and did not measure blood levels of nicotine. Also,
most studies were performed on smokers whose immediate and long-
term smoking history was determined by questionnaires which may
not accurately reflect tolerance and physical dependence (Chapter
IV). In some studies the subjects were deprived of cigarettes, but no
objective measures such as expired carbon monoxide or blood

107


nicotine levels were collected to verify compliance with the depriva-
tion conditions.

Spontaneous Electroencephalogram

Historically, nicotine and ACh were used in animal experiments to
study the cholinergic mechanisms in the midbrain and thalamus
which produced EEG and behavioral activation (Longo, von Berger,
Bovet 1954; Rinaldi and Himwich 1955a,b). The administration of
nicotine produced EEG activation, consisting of desynchronized low-
voltage, fast activity, and behavioral arousal or alerting. These EEG
and behavioral responses resembled those produced by electrical
stimulation of the midbrain reticulomesencephalic activating system
(Moruzzi and Magoun 1949). With the discovery by Eccles, Eccles,
and Fatt (1956) of nicotinic receptors in the Renshaw cell of the
spinal cord, other investigators began to study the precise pharma-
cology of the EEG and behavioral alerting produced by nicotine and
electrical stimulation of the midbrain. Cigarette smoking in humans
also produced EEG desynchronization (Hauser et al. 1958, Wechsler
1958; Bickford 1960) or EEG desynchronization with an increase in
alpha frequency (Lambiase and Serra 1957). By the late 1950s and
early 1960s it was generally known that nicotine or tobacco smoke
caused EEG and behavioral arousal in animals and humans, but
several important issues were unresolved.

The central effects of nicotine were originally thought to result
from its action on the cardiovascular system (Heymans, Bouckeart,
Dautrebande 1931). Early studies found that EEG desynchronization
occurred when the subjects smoked nicotine cigarettes, nicotine-free
cigarettes, or sucked on glass tubes filled with cotton (Hauser et al.
1958; Wechsler 1958). Schaeppi (1968) injected nicotine into the
vertebral artery, carotid artery, and third and fourth ventricles of a
cat's brain and was able to dissociate the effects of nicotine on the
EEG from those on the cardiovascular system. Kawamura and
Domino (1969) demonstrated that the EEG changes induced by
nicotine could be obtained in animals whose blood pressure increase
was blocked. Prevention of release of catecholamines in reserpine-
pretreated animals did not interfere with the EEG desynchroniza-
tion produced by nicotine (Knapp and Domino 1962).

Inhaled tobacco smoke (2-mL samples with about 2 pg/kg of
nicotine) and 2 pg of nicotine injected every 30 set in a cat encephale
isole preparation produced EEG desynchronization. EEG and behav-
ioral activation after cigarette smoke inhalation was also observed in
unanesthetized cats with implanted electrodes (Hudson 1979). Lukas
and Jasinski (1983) found that i.v. doses (0.75 to 3.0 mg) in human
smokers resulted in dose-dependent decreases in alpha (8 to 12 Hz
EEG activity) power and EEG desynchronization. In an inpatient
study where nicotine deprivation was carefully controlled and

108


monitored by measurement of expired carbon monoxide, the smok-
ing of non-nicotine cigarettes did not change the EEG (Herning,
Jones, Bachman 1983), but EEG changes did occur when subjects
smoked nicotine-containing cigarettes. These studies confirm that
nicotine has a direct action on the CNS separate from the cardiovas-
cular effects and that the effects are produced primarily by the
nicotine in inhaled tobacco smoke.

As experimental physiological manipulations, EEG recording, and
EEG quantification techniques improved, the specific nature of the
nicotine-induced cortical EEG changes and their relationship to
behavior were found to be more complex than originally thought.
The desynchronization produced by nicotine (20 to 100 pg/kg) in the
cat was blocked by anterior pontine transections, but not by
midpontine transections (Knapp and Domino 1962). The midbrain
reticular activating system was needed for the cortical EEG desyn-
chronization produced by nicotine. However, larger doses of nicotine
injections also produced synchronous slow high-voltage EEG activity
in the hippocampus (hippocampal theta). Injections of the muscarin-
ic agonist arecoline (20 to 40 mg/kg) in the anteriorly transected
midbrain preparations still produced the hippocampal theta activity
without the cortical desynchronization. Atropine (1 mg/kg) and
mecamylamine (1 mg/kg), but not the ganglionic antagonist trimeth-
idinium (1 mg/kg) block the nicotine induced EEG desynchroniza-
tion in an intact animal. The convulsions observed after nicotine
injections (1 to 5 mg/kg in cats; 0.05 to 0.25 pg/g in mice) (Laurence
and Stacey 1952; Stone, Meckelnburg, Torchiana 1958; Stiimpf,
Petsche, Gogolak 1962; Stumpf and Gogolak 1967) appear to be due
to nicotine's ability in large doses to stimulate muscarinic choliner-
gic receptors in the hippocampus. Because a high concentration of
labeled nicotine binds to hippocampal cells of the cat (Schmiterlow et
al. 1967) and areas adjacent to the hippocampus in the rat (Clarke,
Pert, Pert 1984), the possibility that nicotine-induced limbic electri-
cal activity contributes to its behavioral effects cannot be discounted.

Nicotine's alerting effect on the brain may also involve a peripher-
al component. Electrocortical and behavioral arousal occurs in the
cat within 1 to 2 set after injection of 10 to 15 pg/kg into the right
atrium of the heart, originating in vagal pulmonary C fiber afferents
(Ginzel 1987). The human counterpart to this finding is the
observation by Murphree, Pfeiffer, and Price (1967) that an initial
EEG change occurred within 5 set after cigarette smoke inhalation,
which is shorter than a chest-to-head circulation time. Another input
from the periphery arises from nicotinic sites in the arterial tree.
Injection of small amounts (2 to 4 pg/kg) of nicotine, even as far
away from the brain as into the lower aorta or femoral artery, causes
instantaneous arousal from all types of sleep (Ginzel and Lucas
1980).

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The nicotine-induced release of ACh (Macintosh and Oborin 1953;
Mitchell 19631 may be responsible for the EEG desynchronization in
animals (Armitage, Hall, Sellers 1969). The effect does not appear to
be due to the direct action of nicotine on the cortex because the
cortical cholinergic receptors are largely muscarinic (Kuhar and
Yamamura 1976; Rotter et al. 1979). Lower doses of nicotine (20
pg/kg/30 set for 20 min) induced EEG desynchronization and ACh
release in the cat, whereas higher doses (40 pg/kg/30 set for 20 min)
produced either an increase or decrease in EEG desynchronization
with corresponding increase or decrease in ACh release (Armitage,
Hall, Sellers 1969). The effect of nicotine on the EEG was short lived
relative to the release of ACh. Two separate pathways have been
proposed to explain these results: an ascending cholinergic pathway
mediating the cortical desynchronization and a limbic pathway
mediating the ACh release.

In one strain of mice, C57BL, nicotine increased cortical high-
voltage activity and decreased homovanillic acid (HVA) and 3-
methoxy-4-hydroxyphenthyleneglycol (MHPG) production in a per-
fused brain preparation (Erwin, Cornell, Towel1 1986). The decrease
in HVA and MHPG levels reflects an increase in brain DA and NE
levels. In intact C57BL mice, nicotine decreased locomotor activity
(Marks, Burch, Collins 1983a). Thus, at least in one strain of mice,
nicotine induces an increase in cortical EEG synchronization, a
decrease in locomotor activity, and an increase in brain catechol-
amines. Little evidence relates the cortical desynchronization ob-
served in animals and humans to an increase in catecholamine
changes in the brain.

As trends in neuroscience research have shifted away from
spontaneous EEG recording in animals to intracellular recording,
receptor localization, and binding techniques, the precise quantifica-
tion of the nicotine-induced EEG desynchronization and hippocam-
pal synchronization has not been done. This type of quantification
has been done in humans by power spectral analysis. This technique
quantifies the EEG by the distribution and amplitude of brain waves
at different frequencies. Alpha power includes EEG activity in the 8-
to 12-Hz frequency range. Theta power includes EEG activity in the
4- to ~-HZ frequency range. Beta power includes EEG activity in the
frequency range of 13 Hz and higher.

The comparison of nicotine-induced EEG changes in animals and
humans is complicated by an important methodological difference.
Animals usually have not previously been given nicotine, while in
studies of humans, the subjects always are experienced tobacco
smokers. Moreover, in human studies that included a deprivation
period, nicotine abstinence may have produced electrophysiological
changes that are reversed by smoking or nicotine.

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EEG desynchronization or increased beta power was observed in
smokers after smoking a tobacco cigarette (Hauser et al. 1958;
Wechsler 1958: Bickford 1960; Ulett and Itil 1969). These findings
essentially replicated the animal studies of nicotine. Using power
spectral analysis, Ulett and Itil (1969) also observed a decrease in
theta power and an increase in alpha frequency. The increase in
alpha frequency was previously noted with visual inspection by
Lambriase. However, the increase in theta was not. The subjects in
the study by Ulett and Itil had smoked one pack or more of
cigarettes/day and had been deprived of tobacco cigarettes for 24 hr
when the baseline EEG was recorded. Comparisons of the postsmok-
ing EEG were made with this baseline period. Therefore, the
decrease in alpha frequency and increase in theta power relative to
the data from the postsmoking session may be the result of nicotine
deprivation (Chapter IV).

Knott and Venables (1978) compared the alpha frequencies of
nonsmokers, 12-hr nicotine-deprived smokers. and nondeprived
smokers. They observed a decrease of about 1 Hz in the dominant
alpha frequency of the deprived smokers relative to the nonsmokers
and nondeprived smokers in a passive eyes-closed situation. An
active behavioral task and other frequencies of the EEG were not
studied. Knott and Venables hypothesize that smokers were consti-
tutionally different from nonsmokers. The slower alpha frequency
was interpreted as an arousal deficit, and smoking as compensation
to reduce the arousal deficit. Knott and Venables (1978) and Ulet
and Itil (1969) both found an attentional deficit during tobacco
deprivation.

Herning and coworkers (1983) investigated the EEG changes
related to cigarette smoking in a hospitalized group of healthy
smokers who smoked at least a pack and a half of tobacco cigarettes
with a machine nicotine delivery of 0.8 mg or more. A serial
subtraction task was administered and EEGs were recorded from
subjects in an eyes-open state. Alpha frequency was not affected by
periods of smoking and deprivation. However, theta and alpha power
increased during periods of deprivation and decreased after smoking
tobacco but not placebo cigarettes. The effects were most pronounced
on theta power. Increases in thet.a power occurred as early as 30 min
after the last cigarette, and were of the same magnitude as those
after 10 to 19 hr of nicotine deprivation. The increase in EEG theta
was interpreted to be a sign of tobacco deprivation (Chapter IV).

An indirect method of observing an increase in cortical activation
was the measurement of alpha power changes after tobacco smoking.
A number of investigators reported a decrease in alpha power or
abundance with cigarette smoking (Murphree, Pfeiffer, Price 1967:
Philips 1971; Caille and Bassano 1974, 1976; Murphree 1979:
Herning, Jones, Bachman 1983; Cinciripini 1986). with nicotine

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polacrilex gum (Pickworth, Herning, Henningfield 1986, in press),
and with i.v. doses of nicotine (Lukas and Jasinski 1983). In spite of
differences in the number of cigarettes regularly smoked by the
subjects, the length of tobacco deprivation, the type of tobacco
cigarette smoked during the experiment, and the route of adminis-
tration, nicotine reduced alpha power.

Brown (1968) measured the resting EEG for heavy smokers and
nonsmokers. No cigarett.es were smoked. The EEG of the heavy
smokers had less alpha and more beta activity. Twelve hours of
nonconfirmed deprivation in the heavy smokers did not change the
EEG patterns.

The EEG of neonates of mothers who smoke is not different from
that of neonates of control mothers (Chernick, Childiaeva, Ioffe
1983). Whether acute periods of smoking may affect the EEG of the
child before birth is not known.

In limited animal and human work, individual or species differ-
ences in the effects of nicotine on the EEG have been observed.
Nicotine produced a dose-dependent cortical EEG desynchronization
in C3H mice and an increase in synchronized EEG similar to
hippocampal theta activity in C57BL mice (Erwin, Cornell, Towel1
19861. Both effects have been observed at different doses in the same
preparation (Kawamura and Domino 1969). Lower doses produce
EEG desynchronization, and higher doses produce hippocampal
theta. Tobacco cigarette smoking decreased EEG alpha power in
Type A subjects and increased theta power in Type B subjects
deprived of nicotine for about 4 hr (Cinciripini 1986). The relation-
ship between hippocampal thet,a in animals and cortical theta in
humans is not yet understood. In nondrugged animals cortical
desynchronization and hippocampal theta activity often occur simul-
taneously. Nicotine at low doses produces cortical desynchronization
and at high doses produces both types of EEG activity. Animal data
indicate that nicotine has effects on at least two systems in the brain:
a midbrain area responsible for EEG desynchronization and a limbic
system generating hippocampal theta activity. These findings are
consistent with the observation that some smokers indicate that they
smoke for nicotine's stimulating effects and others smoke for its
sedating effect.s.

Sensory Event-Related Potentials

In animals and humans, the brainstem auditory-evoked potential
technique provides a noninvasive method for studying the effects of
nicotine on primary auditory sensory function. In the rat, nicotine
reduced the amplitudes of Waves III and IV of the brainstem
auditory-evoked response (BAER) iBhargava and McKean 1977;
Bhargava, Salamy, McKean 1978; Bhargava, Salamy, Shah 1981).
Serotoncrgic mechanisms may mediate the nicotine-induced reduc-

112


tion in latency. Lavernhe-Lemaire and Garand (1985) found essen-
tially the opposite. Nicotine increased Waves I-III and did not
decrease Waves IV and V of BAER.

Auditory event-related potentials (AERPs) recorded directly from
the cortex of rat have provided conflicting information about
nicotine's effects on auditory transmission from the inferior collicu-
lus to the cortical areas. Guha and Pradhan (1976), using pentobarbi-
tal anesthesia, found a dose-dependent increase in PI (40 ms) and Nl
(110 ms) of the AERP. Bhargava, Salamy, and McKean (1978), using
chloralose anesthesia with atropine pretreatment, reported no
nicotine-related change in Pl (11 ms), Nl (28 ms), P2 (75 ms), and N2
(121 ms) of the AERP.

After smoking, the Pl (50 ms) of the human AERP is increased
during passive tasks at all intensity levels and the Nl (110 ms) is
increased in both passive and active tasks (Knott 1985). The N2
(about 215 ms) to P2 (about 260 ms) component of the AERP recorded
during a passive task was reduced after cigarette smoking when
compared with data from the baseline deprivation test (Friedman
and Meares 1980). P2 was also reduced by nicotine in the study by
Knott (1985). These components also increased in amplitude as the
tobacco deprivation period was lengthened. Any attempt to relate
this finding to results in the anesthetized rat would be speculative
because AERPs recorded from the cortex of unanesthetized animals
and humans are difficult to compare (Wood et al. 1984). Alterations
in AERP components in the 75- to 150-ms latency range have been
attributed to change in attention. The decrease in the later N2-P2
component is more likely to reflect reduced habituation to auditory
stimuli.

The effects of nicotine on visual event-related potentials (VERPs)
are more complicated than those on the AERPs. In unaesthetized
rabbits, iv. nicotine (0.025 to 0.500 mg/kg) produced a complex
VERP change (Sabelli and Giardini 1972). At 2 min, nicotine
depressed the Pl (100 ms) and the Nl (250 ms). At 5 min, these
components were enhanced. At doses below 0.050 mg/kg, the Nl was
again depressed from 10 to 20 min after the injection. Pretreatment
with catecholamine inhibitors diminished the nicotine-induced
VERP changes. The authors suggested that the effect of nicotine on
VERPs was mediated in part by catecholaminergic mechanisms.

The effects of nicotine on the human VERP using multiple flash
intensities were the focus of four studies. The studies were designed
to test Buchsbaum and Silverman's (1968) concept of stimulus
intensity control and its modulation by nicotine. According to their
theory, sensory processing in different individuals varies in at least
two ways. Some persons, "augmenters," are more sensitive to higher
intensities than to lower intensities, and others, "reducers," are
more sensitive to lower than to higher intensities. Smokers might be

113


one particular type of stimulus processer and may smoke to alter or
normalize stimulus intensity. In all studies the comparison was
between results after 12 hr or more of unconfirmed tobacco
deprivation and those after recent smoking. Components of the
VERP increased after smoking in three studies (Hall et al. 1973;
Friedman and Meares 1980; Woodson et al. 1982) but decreased in
another study (Knott and Venables 1978). The increases and
decreases occurred in components of the same latency range (75 to
250 ms) after flash onset. The fourth study differed only slightly
from the others in that it used a between-subjects and not within-
subject experimental design. Using a single flash intensity, Vasquez
and Toman (19671 also observed a decrease in components IV (I*0 ms)
and V (170 ms) of the VERP when compared with results after 36 hr
of tobacco deprivation. Two studies found a nicotine-induced increase
at earlier components (III-IV and IV-V) for the lower intensities only.
The other study reported an increase in later components (V-VI and
VI-VII) at the higher flash intensities. Knott and Venables (1978)
observed the decrease after smoking in the middle components (IV-V
and V-VI) for the lower intensities. Because of these divergent
results, it is premature to conclude t,hat smokers are exclusively
augmenters or reducers who are attempting to optimally adjust
stimulus intensity by smoking.

Cognitive Event-Related Potentials

Cognitive event-related potentials reflect neural events which
appear to be related to different aspects of cognition, such as
attention and stimulus evaluation. They usually follow the sensory
components of event-related potentials when human subjects are
performing active behavioral tasks. They provide information not
normally available from performance measures such as reaction
time. Increases or decreases in these potentials after smoking can aid
in our understanding the effects of nicotine on performance.

When two task-relevant stimuli are separated by a short interval
(1 to 3 set), a negative slow wave develops between them. In
particular, this contingent negative variation (CNV) develops in
warned or cued reaction times, successive discrimination, and some
language processing tasks. The CNV appears to reflect brain
preparation to process and respond to the second stimulus. Smoked
tobacco and i.v. nicotine either increase or decrease the CNV (Ashton
et al. 1973, 1974, 1980; Minnie and Comer 1978). Extraverted
smokers took longer to smoke and nicotine increased the CNV.
Introverted subjects smoked faster and nicotine decreased the CNV.
Reaction time was inversely correlated with CNV amplitude; that is,
shorter reaction time was associated with larger CNV. With iv.
doses of nicotine (12.5 to 800.0 pg), larger doses produced a decrease
and small doses produced an increase in the CNV in the same

114


subject. O'Connor (1982) studied the effects of smoking on the
orienting (0 wave) and expectancy (E wave) components of the CNV
in introverted and extraverted subjects. The 0 wave was not affected
by smoking. The E wave, recorded in frontal areas, was increased in
extraverted subjects after smoking. The E wave has been interpreted
by some investigators as cortical preparation for a response. Smok-
ing decreased a positive parietal E wave in introverts. Nicotine's
effect on the E wave suggests the possible enhancement of motor
preparation in the extraverted subjects. The decrease of parietal
positivity indicates a possible enhancement of stimulus-processing
capacities in the introverts.

Poststimulus components PZ(O0) and P3(00) were affected by
cigarette smoking and nicotine polacrilex gum. P2 is thought to be
an index of habituation (Hillyard and Picton 1979), and P3 an index
of stimulus evaluation (Johnson 1986). Both components were
reduced in deprived smokers after smoking (Knott 1985; Herning
and Jones 1979). Knott (1985) interprets the reduction in P2 as a
more efficient habituation of sensory screening of relevant stimuli.
The reduction in P3 amplitude after smoking indicates a poorer
evaluation of task-relevant stimuli. The P3 latency and reaction time
were reduced only by cigarettes with higher machine-tested nicotine
yields (Edward et al. 1985). Such data indicate faster stimulus and
response processing. These authors did not report any P3 amplitude
changes. If none were present or P3 was reduced, the argument for
enhanced stimulus processing would be weak. Herning and Pick-
worth (1985) reported both dose-dependent increases and decreases
in P3 amplitude as a function of background noise levels when
deprived smokers chewed nicotine polacrilex gum (4 mg and 2 mg
doses). The respective increase or decrease was blocked by mecamy-
lamine pretreatment. Thus, the effect of nicotine on stimulus
evaluation remains unclear and is perhaps confounded by cognitive
deficits after periods of nicotine deprivation.

Motor Potentials

O'Connor (1986) investigated the effect of tobacco smoking on
motor potential and motor performance. Smoking increased the
motor readiness potential in extraverts, but not in introverts. These
results are consistent with his earlier finding of an increased E wave
in extraverts after smoking. For introverts, smoking improved task
performance, but did not increase the motor readiness potential.

Other Peripheral Effects Relevant to Tobacco Use
In addition to vast central and peripheral effects, cigarette
smoking and nicotine have other peripheral effects that may
contribute to tobacco use. These additional factors have received less

115


research attention, mainly because they involve relatively new
theory or methodological approaches. For example, there is evidence
that direct stimulation of the trachea is important for cigarettes to
satisfy smokers (Rose et al. 1984) (Chapter IV). There is also evidence
that nicotine acts directly on the lung to stimulate afferent neurons
that, in turn, result in skeletal muscle relaxation and electrocortical
arousal (Ginzel 1987). These effects may contribute to the relation-
ship between smoking and stress (Chapter VI). Other research
indicates that smoking affects psychophysiological reactivity, an
integrative mechanism that is different from the classic, physiologi-
cal approach of examining individual systems or pathways. There-
fore, psychophysiological reactivity and its relevance to smoking are
discussed.

Psychophysiological Reactivity and Smoking

Psychophysiological reactivity is emerging as a useful construct in
smoking research, linking basic biological processes (genetic vulnera-
bility, central neurochemical factors) to behavioral coping and other
psychosocial factors. Psychophysiological reactivity refers to a
physiological response to a specific stimulus or as a result of the
absence of stimulation. This response can, in some cases, act as a
stressor. Within the broader conceptual framework of a stress-coping
model of smoking addiction (Shiffman and Wills 19851, smoking
behavior can be viewed both as a potential stimulus and as a coping
response that modulates psychophysiological reactivity.

Studies of psychophysiological reactivity illustrate the value of
controlled laboratory procedures to study person-environment inter-
actions. Psychophysiological reactivity reflects an interaction of the
organism and the environment. It is affected by individual differ-
ences in multiple response modes (physiological, cognitive, behavior-
al) and takes into account the genetic and learning history and
current state of the organism.

This Section reviews two separate but interrelated lines of
psychophysiological reactivity research with humans. The first is the
effect of smoking on psychophysiological reactivity. Related issues
include identification of mechanisms that may help to reveal why
some individuals smoke and the relationship between smoking and
coronary heart disease (CHD). The second research line addresses
the relationship among situational events (general and drug-specif-
ic), psychophysiological reactivity, and relapse.

The effects of smoking on the cardiovascular aspects of physiologi-
cal reactivity have been well documented and appear to be primarily
due to effects of nicotine and carbon monoxide (Suter, Buzzi, Battig
1983; Koch et al. 1980; Rosenberg et al. 1980). In individuals with no
cardiovascular disease, some of the typical effects of smoking and
nicotine are elevated heart rate and blood pressure and a fall in

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fingertip temperature and capillary blood flow (Richardson 1987;
Ashton et al. 1982; Epstein and Jennings 1986; Henningfield et al.
1983).

Accompanying cardiovascular reactions to smoking are cognitive
reactions, including perceptions of relaxation, and anxiolytic, antino-
ciceptive, euphoric, stimulative, and dysphoric effects (Kozlowski,
Director, Harford 1981). Although there is consistency in the
literature with regard to the self-reported emotional changes experi-
enced as a result of smoking, there are clear differences in response
and direction of effects between individuals and within individuals
over time (Best and Hackstian 1978; Gilbert 1979; Gilbert and
Welser, in press). Smoking can produce physiological changes that
are concurrent with subjective tranquilizing effects (Nesbitt 1973;
Shiffman and Jarvik 1984; Gilbert 1979). This phenomenon has led
investigators to emphasize the importance of incorporating physio-
logical, psychological, and environmental factors into more biobeha-
vioral models to better understand the cognitive and physiological
components of reactivity to smoking (Pomerleau and Pomerleau
1984; Baum, Grunberg, Singer 1982; Abrams et al. 1987; Grunberg
and Baum 1985). For example, nicot,ine has direct and indirect
actions on central neuroregulatory systems and has biphasic effects
of both stimulation and blockade. These factors can help explain
effects such as the anxiolytic and antinociceptive phenomena
(Pomerleau 1986) at a cognitive and neurochemical level, while at
the same time resulting in increased heart rate and blood pressure
and decreased perception of muscle tension (Epstein et al. 1984).

In addition to dosage, biphasic, and physiological factors, the
influence of setting and expectancy set, the current state of the
individual (smoking, deprived, stressed, not stressed), and individual
differences in dependence, genetic, demographic, and learning
history can all influence psychophysiological reactivity. For exam-
ple, smoking a 1.3-mg-nicotine cigarette under conditions of mild
sensory isolation produced consistent arousal effects (i.e., elevations
in heart rate and skin conductance level with decreases in EEG
alpha waves) in smokers compared with sham smoking or a
situational control group. However, under conditions of stress, as
induced by intermittent noise bursts, a mixed stimulant (heart rate)
and depressant (EEG, skin conductance) response was observed
(Golding and Mangan 1982). Woodson and coworkers (1986) also
reported that during noise, smoking induced cardiovascular stimula-
tion (i.e., heart rate acceleration, peripheral vasoconstriction) but
electrodermal depression (i.e., lowered skin conductance response
amplitude). These findings are consistent with the conclusions of
Gilbert and Welser (in press) that unidimensional models are
inadequate to explain the effects of smoking.

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In addition to research on the impact of smoking on psychological
and physiological processes, studies have also examined the com-
bined cardiovascular effects of smoking and stress. In this context
the concept of cardiovascular psychophysiological reactivity is used
to help clarify the relationship among stress, smoking, and CHD
(Epstein and Jennings 1986). MacDougall and colleagues (1983)
randomly assigned 51 male smokers to smoking versus sham
smoking and stress versus no stress conditions in a 2 x 2 factorial
design. The stressor was a difficult video game performed under
challenging conditions. Subjects who sham smoked under no stress
showed minimal cardiovascular response. Subjects who smoked
under no stress or who sham smoked under stress evidenced similar
degrees of response of about a 15-bpm increase in heart rate, a 12-
mmHg increase in systolic blood pressure, and a 9-mmHg increase in
diastolic blood pressure. Subjects in the combined smoking and stress
condition had larger increases in all cardiovascular measures. The
combination of mild stress and smoking produced effects that were
twice those of either condition alone. Smoking and stress combined
to increase cardiovascular response in men.

In a followup study of women, using the same 2 x 2 factorial
design, Dembroski and colleagues (1985) found that the combined
effect of stress and smoking produced blood pressure and heart rate
increases that exceeded the sum of the individual effects. However,
because modifications were made in dosage and psychological
challenge, the two studies were not identical. The gender differences
noted could therefore reflect methodological differences, uncon-
trolled factors, or possibly differences between the sexes in response
to the stress and smoking stimuli. Indeed, it has been noted that
females may be more likely than males to smoke to regulate affect
(Ikard and Tomkins 1973), are more likely to relapse after quitting
(Gritz 1986), may differ in biological factors relating to stress
reactivity/sensitivity (Abrams et al. 1987), and show greater changes
in body weight and eating behavior in response to nicotine (Grun-
berg, Bowen, Winders 1986; Grunberg, Winders, Popp 1987). (See
Chapter VII for a discussion of treatment implications of these
possible sex differences.)

In a conceptually related study, the relationship between physio-
logical responses to cognitive (mental arithmetic) and physical (cold
pressor) stressors was examined in female smokers and nonsmokers
who either used or did not use oral contraceptives (Emmons and
Weidner, in press). All subjects showed some physiological response
(heart rate and blood pressure responses) to the stressors, but in
smokers oral contraceptive use significantly enhanced the systolic
blood pressure response to cognitive stress. This finding may be
related to the fact that smokers who use oral contraceptives are 5.6-
times more likely to have a myocardial infarction than are smokers

118


who do not use oral contraceptives, 9.7-times more likely than
nonsmoking users, and 39-times more likely than nonsmokers who
do not use oral contraceptives (Shapiro et 21. 1979; Jain 1976; Ory
1977).

In studies of psychophysiological reactivity, it is critical to identify,
measure, and control for factors that might confound or alter the
intended impact of the independent variables. For instance, time
since last drink and beliefs, expectations, and setting are important
variables to consider in the study of alcohol addiction (Abrams and
Wilson 1979; Abrams 1983; Marlatt and Rohsenow 1980). The 2 x 2
balanced placebo design (Marlatt, Demming, Reid 19731, where
expectancy set (told to expect the drug or told to expect no drug) and
actual content (drug versus placebo) are fully controlled, has been
used extensively in the alcohol addiction field t.o isolate the separate
and interactive elements of cognitive and pharmacologic effects.
With smoking, little is known about the separate and interactive
impacts of expectations of cigarettes' effects versus their actual
pharmacologic effects. This is partially because it is difficult to find a
method of administration that closely resembles smoking but where
the required manipulations to achieve a credible balanced placebo
design can be accomplished.

Another methodological concern is control over the dosage of
nicotine absorbed by the smoker. Nicotine is thought to be the most
important tobacco constituent responsible for the acute effects of
smoking on reactivity, attention and task performance, mood, and
withdrawal following cessation (Perkins et al., in press; Pomerleau,
Turk, Fertig 1984; Hughes et al. 1984). However, in tobacco smoking,
nicotine is accompanied by more than 4,000 other compounds (Dube
and Green 1982) and smokers are known to smoke in individualized
ways (Epstein et al. 1981) (Chapter IV). The coaching of puff
frequency and other attempts to standardize intake of smoke are
imperfect (Perkins et al., in press). An aerosol nasal spray appears to
be a promising alternative to smoking in studies of behavioral and
physiological effects. It allows for rapid uptake through inhalation,
and a dose-response study indicates patterns of heart rate, blood
pressure, and serum nicotine levels that are very similar to those
obtained by smoking cigarettes of equivalent nicotine content
(Perkins et al., in press).

Perkins and coworkers (in press) studied the separate and interac-
tive effects of nicotine administered by nasal aerosols and stress on
psychophysiological reactivity. The authors note that the previous
studies (MacDougall et al. 1983; Dembroski et al. 1985) could be
confounded because smokers usually smoke more under stress and
therefore they may inhale more nicotine or alter their smoking in
other ways when stressed (Mangan and Golding 1978; Rose, Ananda,
Jarvik 1983) (Chapter VI). In other words, the additive effects of

119


stress and smoking on physiological responses could have resulted
from uncontrolled changes in smoking pattern between the smokers
in the no-st.ress and stress conditions. Perkins and colleagues (in
press) studied 12 male smokers in a repeated-measures design, where
subjects received all 4 conditions (stress plus nicotine, stress plus
placebo, rest and nicotine, and rest and placebo) on separate days
with the order of condition counterbalanced within subjects. Follow-
ing the methodology of previous studies of psychophysiological
reactivity, the researchers used an active stressor consisting of a
video game under conditions of competitive challenge. Nicotine was
administered in measured l.O-mg doses by the aerosol nasal method
(Perkins et al., in press). Consistent with observations of MacDougall
and coworkers (1983), results were additive for heart rate reactivity.
However, effects were less than additive for systolic and diastolic
blood pressure.

Taken together, the studies of the effects of smoking cigarettes and
of nicotine aerosol stimuli on the physiological responses of adult
males demonstrate a consistent effect for the stimuli alone, additive
in combination with stress on heart rate, and additive or less than
additive with stress on blood pressure. There is some suggestion that
effects may be more than additive for women, but this finding
requires replication.

Psychophysiological Reactivity, Smoking Cessation, and
Relapse

Psychophysiological reactivity also serves as a conceptual frame-
work to study relapse after cessation from smoking (Shiffman 1986b;
Abrams 1986). Individual differences in psychophysiological reactivi-
ty and associated coping responses, as a function of general and
smoking-specific stressful stimuli, have been hypothesized to medi-
ate relapse. For example, smokers who smoke more when stressed
might be particularly vulnerable to relapse (Pomerleau, Adkins,
Pertschuck 1978). This idea is consistent with the observation that
relapse may be triggered by life stress events and other psychosocial
demands (Ockene et al. 1982) and by high-risk situations including
negative emotions, social conflicts and pressures, and the presence of
alcohol or smoking cues (Marlatt and Gordon 1985; Shiffman 1979,
1982,1984. 1986a; Abrams et al. 1986). If certain psychophysiological
reactivity responses distinguish potential abstainers from relapsers,
cessation may be better maintained by identifying "relapse-prone"
individuals (Chapter VII).

Stressful environmental demands, sensitivity of the individual to
these demands, and the repertoire of coping responses are important
factors in relapse (Shiffman and Wills 1985; Abrams et al. 1987).
These same factors also may contribute to initiation of smoking
among adolescents. Wills (1985) provides evidence for the stress-

120


coping model of smoking in adolescence, relating both stress and
coping patterns to substance use. Results are consistent wit.h other
findings that, in addition to peer pressure to smoke, adolescents
actively seek methods of coping with their perceptions of stress
(Wills 1985; Friedman, Lichtenstein, Biglan 1985; Botvin and
McAlister 1981). Although these survey studies are consistent with
the notion of smoking as a means of coping with psychophysiological
reactivity to environmental demands, research has not yet measured
reactivity in adolescents prior to smoking onset.

Observational and retrospective studies of relapse have identified
other   smoking-specific   stressful   stimuli   and   cogni-
tive/psychophysiological measures of reactivity that are relevant to
relapse. Situations or stimuli that cue smoking and are associated
with relapse include pharmacologic dependence and withdrawal
symptoms (Jarvik 1977; Pomerleau and Pomerleau, in press; Hughes
et al. 19841, stimuli previously associated with smoking (e.g., coffee
drinking, alcohol) (Shiffman 1984, 1986a; Best and Hakstian 19781,
and urges to smoke (Myrsten, Elgerot, Edgren 1977). Situational
stimuli may or may not have previously been paired with smoking
and may or may not include smoking cues as a trigger for relapse.

Substance use cues themselves (e.g., the sight and smell of
cigarettes) also may precipitate relapse, perhaps in combination with
other stressful stimuli or in a vulnerable individual (Shiffman 1986b;
Abrams et al. 1987). Models of how substance use cues are related to
relapse have been proposed on the basis of classical, operant, and
social learning principles. Reactions may be conditioned to stimuli
repeatedly paired with smoking, resulting in craving and physiologi-
cal reactivity in their presence and moderated by dependence,
tolerance, and nonpharmacologic withdrawal (Siegel 1983; Cooney,
Baker, Pomerleau 1983; Gritz 1980). Psychophysiological reactivity
to smoking cues could mimic the prior drug response (Wikler 19651,
result in a drug-opposite (compensatory) response (Siegel 19831, or
have other effects on psychological processes such as perceived
anxiety, urges to smoke, and self-efficacy in resisting relapse
according to a social learning model of relapse (Marlatt and Gordon
1985).

Abrams and colleagues (1987) studied the psychophysiological
reactivity and behavioral coping responses of male and female
relapsers and quitters in four simulated situational contexts: general
social situations, smoking-specific negative emotional and interper-
sonal role-plays, high-demand social stress, and relaxation. Com-
pared to abstainers, relapsers had higher heart rates and higher
perceived anxiety and were rated as less skillful at coping in the
smoking-specific intrapersonal (negative affect) situations. There
were no differences on any measures in the high-performance-
demand general-social-stress procedure. There were some differences

121


in heart rate and self-reported anxiety in the general social
situations and in heart rate in the relaxation interval, with relapsers
having higher levels than abstainers. Abstainers and relapsers did
not differ in heart rate, perceived anxiety, or coping skills in the
high-demand social anxiety procedure, but they did differ in the
other situations. The results suggest that selected situational
demands prompt situation-specific psychophysiological changes.

Rickard-Figueroa and Zeichner (1985) used a within-subjects
design to examine the responses of smokers to a confederate of the
experimenter lighting and smoking the subject's preferred brand of
cigarette behind a glass window. Cigarette paraphernalia were
piaced adjacent to the subject but smoking was not permitted until
after the session. The cue exposure manipulation resulted in higher
urges to smoke, increased systolic and diastolic blood pressure, and
increased heart rate variability compared with a no-cue condition.
Urges were significantly positively correlated with diastolic blood
pressure, the use of active mastery to cope with urges, and the more
rapid smoking of a standard cigarette after the trial.

In a study that shows some evidence for a conditioned response,
Saumet and Dittmar (1985) measured finger-pulse amplitude, a
measure of peripheral vasoconstrictive activity, while subjects
placed an unlit cigarette into their mouths and waited for it to be lit.
Heavy smokers showed an anticipatory vasoconstrictive response to
the cigarette compared with light smokers and nonsmokers.

Abrams and colleagues (in press) used smoking cues and a social
st,ressor to simulate an interpersonal situation with high risk for
relapse. Relapsers, abstainers, and never smokers were examined for
psychophysiological reactivity. Compared with controls (never smok-
ers), relapsers had significant heart rate reactivity, stronger urges to
smoke, and subjective anxiety. Trained raters, unaware of subject
smoking status, judged relapsers as having significantly less effec-
tive coping skills to resist smoking. In a second study, the same
assessment was used prospectively in a treatment outcome context
to determine whether patt.erns of psychophysiological reactivity
could discriminate between quitters who maintain abstinence from
those who do not. Both heart rate reactivity and subjective anxiety
were greater in quitters who relapsed at 6-month followup compared
with those who continued to abstain. The groups did not differ with
regard to urges to smoke or behavioral judgments of coping skill.
Thus, the two studies were consistent, for heart rate and perceived
anxiety but not for urges or objective ratings of coping effectiveness.

In a reanalysis of the heart rate data from Abrams and coworkers
(in pressj, Niaura and colleagues (in press) examined beat by beat
event-related heart rate during the period immediately before and
for the 10 set following the lighting of a cigarette by a confederate
(subjects did not smoke throughout). Prospective relapsers showed a

122


strong decelerative trend at the point of lighting, whereas prospec-
tive abstainers did not. The results may reflect a conditioned
compensatory response (Siegel 1983) or some other information
processing/attentional phenomenon (Sokolov 1963; Knott 1984). In
another treatment, study, Emmons (1987) examined smokers' cardio-
vascular reactivity to mental arithmetic or deep knee bends before
and 6 months after smoking cessation. There was no change in
reactivity (heart rate, systolic and diastolic blood pressure) to either
stressor before and after quitting. Heightened pretreatment heart
rate reactivity significantly discriminated relapse at g-month follow-
UP.

Individual differences in psychophysiological reactivity may influ-
ence the likelihood of relapse. This possibility is discussed in Chapter
VII.

Summary and Conclusions

1. Nicotine is a powerful pharmacologic agent that acts in the
brain and throughout the body. Actions include electrocortical
activation, skeletal muscle relaxation, and cardiovascular and
endocrine effects. The many biochemical and electrocortical
effects of nicotine may act in concert to reinforce tobacco use.
2. Nicotine acts on specific binding sites or receptors throughout
the nervous system. Nicotine readily crosses the blood-brain
barrier and accumulates in the brain shortly after it enters the
body. Once in the brain, it interacts with specific receptors and
alters brain energy metabolism in a pattern consistent with the
distribution of specific binding sites for the drug.

3. Nicotine and smoking exert effects on nearly all components of
the endocrine and neuroendocrine systems (including catechol-
amines, serotonin, corticosteroids, pituitary hormones). Some
of these endocrine effects are mediated by actions of nicotine
on brain neurotransmitter systems (e.g., hypothalamic-pitu-
itary axis). In addition, nicotine has direct peripherally mediat-
ed effects (e.g., on the adrenal medulla and the adrenal cortex).

123


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CHAPTER IV

   TOBACCO USE
AS DRUG DEPENDENCE

145


CONTENTS

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Cigarette Smoking: Controlled Drug Self-
Administration ................................................... 149
  Measurement of Cigarette Smoking .................... 150
  Characterization of Cigarette Smoking Behavior ... 153
  Patterns of Puffing and Inhaling ....................... 155
  Dose-Related Determinants of Tobacco Intake ....... 158
  Control of Nicotine Intake ................................ 158
     Smoke Concentration ................................. 159
    Cigarette Length ....................................... 161
    Cigarette Brand ........................................ 161
    Cigarette Yield of Nicotine ......................... 162
     Urine pH ................................................ 163
    Tobacco Administration and Deprivation ....... 164
     Nicotine Pretreatments .............................. 165
    Nicotine Antagonist Pretreatments .............. 166
  Effects of Nonnicotinic Drugs on Cigarette
   Smoking ...................................................... 166
  Effects of Nonnicotine Constituents of Tobacco
   Smoke and Citric Acid Aerosol ....................... 168

Nicotine: Psychoactivity, Reinforcing and Related
Behavioral Mechanisms of Nicotine Dependence . . . . . . 169
  Interoceptive, Discriminative, and Subjective Effects
   of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
  Drug Discrimination Testing in Animals . . . . . . . . . . . . . 171
    Specificity of the Nicotine Stimulus.. . . . . . . . . . . . 171
    Peripheral Versus Central Discriminative
      Stimulus Effects of Nicotine . . . . . . . . . . . . . . . . . . . . 173
    Interactions with Noncholinergic Neurons.. . . .175
  Subjective Effects of Nicotine in Humans . . . . . . . . . . . . 175
    Psychoactivity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . 176
    Sensory Effects of Nicotine.. . . . . . . . . . . . . . . . . . . . . . . . 178
  State-Dependent Learning . . . . , . . , . . . . . . . . . . . . . . . . . . . . . . . . . 180
  Nicotine as a Positive Reinforcer . . . . . . . . . . . . . . . . . . . . . . . 181
     Animal Studies of Nicotine as a Reinforcer . . 182
     Human Studies of Nicotine as a Reinforcer . . 192
  Nicotine as an Aversive Stimulus . . . . . . . . . . . . . . . . . . . . . . 192

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Nicotine as an Unconditioned Stimulus.. . . . . . . . . . . . . . 194
  Conditioned Place Preference and Aversion.. . 194
  Conditioned Taste Aversion and Rapid
   Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . 195

Nicotine: Withdrawal Reactions (Physical
Dependence) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Criteria for Physical Dependence on Nicotine and
  Clinical Characteristics of the Withdrawal Syn-
   drome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
  Retrospective Survey Data . . . . . . . . . . , ,. . . . . . . . . . . . . . . . . . . . 199
Prospective Data From Laboratory and Nonlabora-
  tory Studies . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .201
  Time Course of Responses to Nicotine Abstinence. 204
Alleviation of Withdrawal Symptoms by Cigarette
  Smoking.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Relationship Between Preabstinence Nicotine In-
  take and Magnitude of Withdrawal Syndrome . . .206
Smokeless Tobacco Withdrawal Syndrome.. . . . . . . . . . . 207
Nicotine Polacrilex Gum: Treatment and Physical
  Dependence.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
    Treatment of Withdrawal Symptoms.. . . . . . . . . . . 208
    Maintenance of Physical Dependence . . . . . . . . . . .209
  Tobacco Craving.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . 210

Alternate Nicotine Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . .212
  Kinds of Nicotine Delivery Systems. . . . . . . . . . . . . . . . . . . . 212
Safety of Alternate Nicotine Delivery Systems . . . . .213

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

References . . . . . . . . . . . . . . . . . . . . . . . . . ..,...... . . . . . . . . . . . . . . . . . . . . . . . . . 217

148


Introduction

This Chapter reviews the evidence that tobacco is a pharmacologi-
cally addicting substance and that tobacco use can be considered a
form of drug addiction. Specific criteria to identify a substance as
pharmacologically addicting are discussed in Chapters I and V. In
brief, the criteria are: (1) that highly controlled or compulsive
patterns of drug taking occur, (2) that a psychoactive or mood-
altering drug is ingested by use of the substance and is involved in
the resulting patterns of behavior, and (3) that the drug is capable of
functioning as a reinforcer that can directly strengthen behavior
leading to further drug ingestion. Addicting drugs can be character-
ized by other properties that include the following: they can produce
pleasurable effects in users, they can cause tolerance and physical
dependence, and they can have adverse or toxic effects. Drawing
upon data from studies of tobacco and nicotine, involving both
humans and animals, the present Chapter reviews the evidence that
tobacco meets the criteria as a pharmacologically addicting sub-
stance. A specific comparison of tobacco to other pharmacologically
addicting substances is provided in Chapter V.

Cigarette Smoking: Controlled Drug Self-Administration

Highly controlled or compulsive drug use refers to drug-seeking
and drug-taking behavior that is driven by strong, often irresistible
urges. It can persist despite a desire to quit or even repeated
attempts to quit.

Basic observations and experimental research indicate that ciga-
rette smoking is not a random or capricious behavior that simply
occurs at the will or pleasure of those who smoke. Rather, smoking is
the result of behavioral and pharmacologic factors that lead to
highly controlled or compulsive use of cigarettes. The highly
consistent patterns of cigarette smoking illustrate the controlled
nature of the behavior. For example, following initiation of smoking
the individual gradually increases cigarette intake over time until
he or she achieves a level that remains stable, day after day, during
the smoker's lifetime (Schuman 1977; US DHHS 1987a). The
dependent smoker tends to adopt a pattern in which the initial
cigarette of the day is smoked soon after waking (Fagerstrbm 1978)
and in which smoking throughout the day is regular from day to day
(Griffiths and Henningfield 1982; Griffiths, Henningfield, Bigelow
1982). "Occasional" cigarette smoking (or "chipping") occurs just as
does occasional use of other addicting drugs (see Chapter V);
however, the 1985 National Health Interview Survey showed that
only 10.6 percent of current smokers smoke 5 or fewer cigarettes/day
(unpublished data, Office on Smoking and Health; see also Russell
1976 and US DHHS 1987a).

149


Strong evidence that cigarett,e smoking is a highly controlled or
compulsive behavior is provided by survey data showing that a
majority of smokers have tried to quit or at, least would like to quit.
For example, several Gallup surveys have shown that a large
majority of smokers report a desire to quit smoking; in fact, the
proportion of smokers who would like to quit increased from 66
percent in 1977 to 77 percent in 1987 (Gallup 1987), perhaps because
of a declining social acceptability of smoking and the growing
awareness of the health hazards of smoking. In addition, the 1986
Adult Use of Tobacco Survey (US DHHS 1987b) showed that 65
percent of cigarette smokers had made at least one serious attempt
to quit; another 21 percent said that they would try to quit "if there
were an easy way to do so" (Fiore et al., in press; US DHHS 1986).

The compulsive nature of cigarette smoking is most apparent in
extreme cases: for example, the laryngectomized patient who, having
already suffered severe consequences of smoking, continues to smoke
through a tracheostomy hole. Similarly, 50 percent or more of
patients recovering from surgery for a smoking-related disease (e.g.,
cancer, cardiovascular disease) resume smoking while in the hospital
or shortly after discharge (Burling, Singleton et al. 1986; West and
Evans 1986).

In this Section, the behavioral process of cigarette smoking and
the factors which determine the course of the behavior are described.
Evidence that cigarette smoking is repetitious and stereotypic,
common features of compulsive drug use, is reviewed in this Section,
as well as evidence that actions of nicotine are responsible for
patterns of smoking behavior. Initially, however, it is necessary to
briefly review the methods by which the behavioral process of
cigarette smoking is studied, as well as the main findings from such
studies.

Measurement of Cigarette Smoking

Cigarette smoking behavior may be analyzed at different levels
ranging from epidemiological surveys to the analysis of cigarette
puffing. In fact, many thousands of scientific articles have been
published in which some aspect of cigarette smoking is described.
Much of this research has been reviewed in the tobacco research
compendia of Larson and his colleagues (Larson, Haag, Silvette 1961;
Larson and Silvette 1968, 1971, 1975), a previous report of the
Surgeon General (US DHEW 1979), several monographs of the
National Institute on Drug Abuse (NIDA) (Jarvik et al. 1977;
Krasnegor 1978,1979a,b,c; Grabowski and Bell 1983; Grabowski and
Hall 1985) and in articles by others (Russell 1971, 1976; Gritz 1980;
Henningfield 1984).

It is characteristic of drug dependence that the drug-seeking and
self-administration behaviors become stereotypical and automatic in

150


Tobacco campuses:
1 Cigarette constituents
  o ??????? matter
  o Nlwtfnic alkyloids
   o Addltlves

2 Pyrolysis products
   o Carbon dioxide
   o Carbon monoxide

  Filter
1_^_. --

AIM dilution /
and coolrng ua
porous paper

\ To lungs, where
absorption occurs

Absorption factors:

o Inhalation amount
o Inhalation depth
o lnhalatlon duration
o pH of smoke
o Absorption characteristics
of indlvtdual constituents

FIGURE l.-Production and fate of cigarette smoke
        constituents

NOTE Descnpl~on of complexity of process by whxh n~cot~nr is extracted from c+we+te. Amount of nwotme
ultimately absorbed 1s as much a function of smoker beha\lor as of cigarette charactenstlcs
SOURCE: Henningfield (lY841

appearance; cigarette smoking is no exception. The behavior of
lighting, smoking, and extinguishing cigarettes, including puffing
and inhaling, also becomes regular in smokers over time. The
measurement techniques that permit such conclusions, however,
must address a complex behavior. There are many variables (e.g.,
number of puffs, depth of inhalations) that might change and
thereby affect the intake of tobacco smoke and its various constitu-
ents (e.g., nicotine, tar, carbon monoxide (CO)). As shown in Figure 1,
the process of producing cigarette smoke constituents itself is
complex (see US DHEW 1979; US DHHS 1981, for a more thorough
discussion of these factors). This complexity emphasizes the impor-
tance of the use of careful measurement and multiple measures to
ensure accurate characterization of cigarette smoking.

Quantification of cigarette smoking behavior has improved with
the development of automated measurement techniques. These
techniques permit the measurement of puffing and inhalation both
in the laboratory (Gust, Pickens, Pechacek 1983; Epstein, Dickson,
Stiller et al. 1982; Creighton, Noble, Whewell 1978; Herning, Hunt,

151


Jones 1983; Henningfield and Griffiths 1979; Puustinen et al. 1987)
and outside the laboratory (Henningfield et al. 1980; Grabowski and
Bell 1983). Puffing behavior is generally measured by having
subjects smoke through cigarette holders that measure air flow by
use of either temperature-sensitive thermistors (Gritz, Rose, Jarvik
1983; Fagerstrom and Bates 1981) or pressure-sensing transducers
(Henningfield and Griffiths 1979; Gust, Pickens, Pechacek 1983a;
Rawbone et al. 1978). Inhalation behavior has been measured by a
variety of techniques, including mercury strain gauge pneumogra-
phy (Rawbone et al. 1978; Herning et al. 1983), head- and arms-out
whole-body plethysmography (Adams et al. 1983), and impedance
(Nil, Buzzi, Battig 1986) and inductive plethysmography (Herning,
Hunt, Jones 1983; Tobin and Sackner 1982; Tobin, Jenouri, Sackner
1982). Other methods include the use of inert gas radiotracers to
determine the amount of smoke inhaled (Sheahan et al. 1980;
Woodman et al. 1986) and a sensor for directly measuring the
concentration of smoke particles in the holder before puffing
(Jenkins and Gayle 1984).

These procedures have proved to be valuable and reliable methods
of measuring smoking behavior (Woodman et a!. 1984; Herning,
Hunt, Jones 1983). Comparisons of data obtained when simply
observing smokers to data obtained when using the mechanical
devices indicate that such automated measuring techniques are
valid. Such comparisons reveal consistent findings on measures such
as number and duration of puffs and even of patterns of puffing
within cigarettes (Henningfield and Griffiths 1979; Griffiths and
Henningfield 1982). However, other research suggests that the
devices may alter certain characteristics of smoking such as intensi-
ty of puffing (Tobin and Sackner 1982; Ashton, Stepney, Thompson
1978; Ossip-Klein, Martin et al. 1983). In addition, some smoking
behaviors, such as blocking the ventilation holes of filters of low-
yieid cigarettes (which can markedly influence nicotine and tar
intake from the cigarette) are thwarted by the use of a cigarette
holder. Nonetheless, such measurements are useful and appear to
provide valid means of evaluating the effects of specific experimental
manipulations.

Measurement of the intake of cigarette smoke constituents may
also be obtained by analysis of various biological fluids (saliva, urine,
or blood) and expired air. Chapter II reviewed the methods and
practical issues of using such specimens to assess resulting levels of
nicotine, cotinine (a nicotine metabolite), CO, and other tobacco-
associated compounds (see also Jarvis et al. 1987; Benowitz 1983).

Use of the methods described above has led to a much better
understanding of how cigarettes are smoked and factors that affect
intake of smoke constituents such as CO and nicotine. In addition,
these methods permit conclusions regarding which aspects of smok-

152


ing are most robust across individuals, which aspects are strongly
influenced by pharmacologic factors, and which aspects appear to be
determined by other factors. Some of these findings are reviewed in
subsequent sections.

Characterization of Cigarette Smoking Behavior

Although the process of smoking a cigarette may appear to be a
simple behavior, it is actually a complex series of events; a full
characterization requires the measurement of a variety of interde-
pendent indices of frequency, duration, and volume. Even the act of
taking a single puff is complex. Typically, a smoker puffs a volume of
smoke into the mouth, where it is held for a short period of time
(Guillerm and Radziszewski 1978; Medici, Unger, Riiegger 1985). The
puff itself can occur at any point during inhalation, although most
commonly it occurs toward the beginning of an inhalation (McBride
et al. 1984; Guillerm and Radziszewski 1978). During inhalation, the
puff is diluted with ambient air which may be inhaled through the
nose, the mouth, or both (Rodenstein and Stanescu 1985; McBride et
al. 1984; Adams et al. 1983). The postpuff inhalation is generally
longer and larger in volume than normal inspirations (Rodenstein
and Stanescu 1985; McBride et al. 1984). After a variable period of
breath holding, the smoker exhales, usually through the mouth
(Rodenstein and Stdnescu 1985).

All of the above-mentioned behavioral factors can alter nicotine
absorption. The likely impact of some factors is obvious (e.g., number
of puffs taken) (Kozlowski 1981); others are much more subtle (e.g.,
puff shape, which is a function of the air flow rate over time)
(Creighton and Lewis 197813). Analogous but distinct from puffing
factors are inhalation factors (e.g., depth and duration, dilution of
the puff with ambient air) which can also determine the amount of
tobacco smoke constituents which are absorbed. Table 1 lists several
measures of cigarette smoking that have been objectively defined
and measured.

The relationships among these behavioral measures have been
studied. For insta.nce, duration and volume of puffing are generally
highly correlated although they vary somewhat from smoker to
smoker (Gust and Pickens 1982; Epstein et al. 1982; Adams et al.
1983; Nemeth-Coslett and Griffiths 1985; Gust, Pickens, Pechacek
198313; Gritz, Rose, Jarvik 1983). Peak smoke flow rate has been
reported to be moderately correlated with puff volume and weakly
correlated with puff duration (Gritz, Rose, Jarvik 1983). The
relationship between puff volume and interpuff interval is much
more variable (Adams et al. 1983; Gust, Pickens, Pechacek 1983b),
and puffs per cigarette and puff duration have been found to be
inversely related (Lichtenstein and Antonuccio 1981).

153


TABLE l.-Behavioral measures of cigarette smoking

Puffing behavior              Inhalation behavmr

Puffsicigarette               Inhalation volume

Interpuff interval             Inhalation duration


Puff duration               Breathhold duration

Butt length we~ghti          Lung exposure duration


Puff volunle              Percent of puff inhaled

Puff shape

Puff flow rate (puff intensity1

Peak flow rate ~pressure)

Latency to peak flow rate \pressure,

Percent puffing time

When the smoking of individual cigarettes is studied, the mea-
sures of cigarette smoking behavior and the resulting levels of
biochemical markers have also been found to be highly correlated.
For example, four studies found positive correlations between one or
more of the behavioral measures and plasma nicotine levels (Pomer-
leau, Pomerleau, Majchrzak 1987; Sutton et al. 1982; Bridges et al.
1986; Herning et al. 1983). Using another approach, Zacny and
associates (1987) independently varied three aspects of smoking-
puff volume, inhalation volume, and lung exposure duration. They
found that increases in puff volume (from 15 to 60 mL) produced
proportional increases in plasma nicotine level, whereas increases in
inhalation volume (from 10 or 20 to 60 percent of vital capacity) or
lung exposure duration (from 5 to 21 set) had no such effect.

CO intake (measured either from expired air or blood samples) also
tends to be positively related to measures of smoking behavior,
including total puff volume (Gust and Pickens 1982; Guillerm and
Radziszewski 1978; Xl, Buzzi, Battig 1984; Woodman et al. 1986) and
mean puff volume (Zacny et al. 1987; Zacny and Stitzer 1986).
McBride and coworkers (1984) found moderate correlations (r = 0.36
to 0.45) between CO boost and other measures of ventilation (tidal
volume, minute ventilation, and prepuff expiratory volume). These
studies illustrate some of the ways that specific aspects of cigarette
smoking can affect absorption of smoke constituents. These mea-
sures have been used to scientifically describe many features of
cigarette smoking. A summary of findings that have emerged from
such studies is presented in the next Section.

154


Patterns of Puffing and Inhaling

Several studies have characterized the behavior of cigarette
smoking in and outside the laboratory. The values of the most
frequently measured variables are shown in Table 2. Despite a wide
range of variations among studies, including differences in subject
population (age, gender, smoking hist,ory, type of cigarette smoked),
experimental setting, method used to collect the measurements,
apparatus calibration procedures, and operational definitions of the
measured variables, the findings among studies are strikingly
consistent.

Over the course of smoking each cigarette there are striking
consistencies from cigarette to cigarette, both within and between
individuals. For example, during the smoking of a single cigarette,
the duration of each puff tends to decrease and/or the time between
each puff (interpuff interval) tends to increase (Graham et al. 1963;
Griffiths and Henningfield 1982; Nemeth-Coslett and Griffiths 1985;
Herning et al. 1981; Gust, Pickens, Pechacek 1983b; Woodman et al.
1986; Buzzi, Nil, Battig 1985; Adams et al. 1983; McBride et al. 1984;
Chait and Griffiths 1982a). These trends were also found in
nonlaboratory observations by Schulz and Seehofer (1978).

Although these observations reflect a tendency to decrease overall
intensity of smoking over the course of the cigarette, the specific
factors which produce such effects remain to be fully elucidated. The
pattern has been hypothesized to be related to the nicotine dose per
puff (Rickert et al. 1983; Russell et al. 1975; Chamberlain and
Higenbot,tam 1985), because the nicotine concentration of smoke
increases as the cigarette is smoked (Kozlowski 1981). However,
experimental studies suggest that within-cigaret,te changes in puff
intensity are not a simple function of the nicotine dose per puff
(Nemeth-Coslett and Griffiths 1984a,b, 1985). Furthermore, puff
volume may not be controlled by the same factors as puff duration
(Nemeth-Coslett and Griffiths 1985). Thus, the orderliness of the
behavior may be due to a variety of factors.

Various other aspects of puffing and inhaling during the smoking
of single cigarettes have been studied and provide further informa-
tion that helps to characterize this complex behavioral process. For
example, puff shape (puff intensity over time) (McBride et al. 1984),
latency to peak puff pressure (Buzzi, Nil, BBttig 1985), and inhala-
tion volume and duration (Adams et al. 1983) did not change over the
course of smoking single cigarettes. The volume expired from puff to
puff during and immediately after puffing (before inhalation) was
lower for early puffs than for later puffs (Adams et al. 1983).
Woodman and colleagues (1986) reported that the amount of smoke
actually inhaled (range, 46 to 88 percent of puff volume) decreased
proportionately with puff volume as cigarettes were smoked. Finally,
significant changes from cigarette to cigarette in puff volume and

155


TABLE 2.-Published values of common measures of smoking

Study

Number      Puffs/
of subjects    cigarette

Interpuff
mterva1
b32)

Cigarette
duration
kc)

Puff
duration
isec)

Puff
volume
(mLt

Peak
flow
imL/swI

Rawbone et al (1978)                 12         10         41                    1.8

Rawbone et al. (1978~                 9         10         35                    2.1         43
Woodman et al. (1986)                 9         13         18         254         1.9        49                 413
Nemeth-Coslett et al. (1986~             8          8         64         414         18

Nemeth-Coslett et al 11986b)             8         8         47         362         1.4
Nil, Wwdson, Battig (19861             132         13         28                    2.2         30         28        560

Jarvik et al. (1978)                   9         10

Russell et al. (198Ob)                 10         11         35
Ashton. Stepney. Thompson (1978)         14                   24                    1.5

Schulz and Seehofer 11978)             100         11         50                    1.4

Schulz and Seehofer (19781             218         12         42                    1.3
Henningfield and Grifliths (19811           8         10         39         351         1.0
stepney (1981)                     19         13                   400                   38
Battig, Buzzi, Nil (1982)               110         13         26                    2.1         40
Epstein et al. (1982)                 63         13                              2.4         21
Russell et al. (1982)                  12         15         26         324         2.3        40
Gritz. Rose, Jarvik (1983)               8         9         47                    2.2        66         48
OsipKlein, Martin et al. (1983)           9         8                              1.4
OssipKlein. Martin et al. (1983)           9         12                              1.9

Guillerm and Radziszewski (1978)          8         12         41                    1.9         39         35        918
Gust, Pickens. Pechacek (1983b)           8         9         40                    1.6        44

351

339

390

393


Study


Adams et al. (1983)
Moody (1984)
Nil, Buzzi, Battig (19841

Number
of subjects


  10

  517

  20

Puffs.1
cigarette




  9

15

Interpuff
interval
bed



26

26

26

Cigarette
duration
bec)





232

Puff
duration
b32)



1.9

2.1

1.6

Puff
volume
(mL1



44

44

40

Peak
flow
(mL/sec)







40

Inhalation
volume
(mL)



614

McBride et al. (1984)                  9         16         25         352         2.1         42
Medici, Unger. Ruegger (1985)            17         14         19                    2.2         43         31
Burlmg et al. (1985)   ,               24         12         28         330         1.7
Nil, Buzzi, BBttig (1986)               117         13         22                    2.1         42         36
Hughes et al. (1986bl                 46         11                              1.6
Bridges et al. (1986)                 108         11                                       56

Puustinen et al. (1986)                11         13         22                    2.3         44
Hildmg (19561                     27         10

4.5a

Mean                                11         34         346         1.8        43         36        591
Median                               11         28         351         1.9        42.5        35.5       560
Range                               8-16       l&64       232-414       I.&24      21-66       2MR      413-918

NOTE. Data were taken from the baselme phase (or placebo treatment) of studies Involving an experimental manipulation, with at least eight SubJects Values are rounded off to the nearest unit.
and in some cases. were calculated from other variables or estimated from data presented in figures; m&ng values indicate that the vnnable was not measured or was not presented in the publlshrd
study


inhalation volume, as well as their ratio, were reported for individu-
al subjects over the course of a 4-hr smoking session (Herning, Hunt,
Jones 1983).

Dose-Related Determinants of Tobacco Intake

As the preceding material shows, cigarette smoking is a complex
but orderly behavior; it may be qualitatively and quantitatively
described. Furthermore, the behavioral process of tobacco smoke
self-administration substantially determines the amount of smoke
that is actually consumed. Similarly, the behavior of smoking may
change in response to factors related to the delivered smoke and/or
nicotine dose. These interactions are described in the present section.
Much of this research has addressed issues concerning the manipula-
tion of some aspect of cigarette and/or nicotine dose level. Such data
are relevant to comparing this form of drug self-administration with
other forms of drug self-administration, because one of the basic
findings in studies of drug-seeking behavior is that the dose may
affect the behavior. For example, when the dose (quantity) of a
psychoactive drug is high, fewer doses are generally taken compared
to when the dose is very low (Griffiths, Bigelow, Henningfield 1980;
Chapter V).

With regard to cigarette smoking, the control and measurement of
cigarette dose level is more complex than is the case with most other
forms of drug delivery. For example, in opioid and alcohol studies,
the amount of the morphine injected and volume of alcohol
consumed can be precisely measured, but cigarette smoke can vary
in levels of CO, tar, nicotine, and many other potentially important
constituents (see Figure 2). The total smoke dose is positively related
to the number of puffs taken per cigarette. However, total smoke
dose might be changed by diluting the smoke with air or changing
the number of available cigarettes. Alternatively, the smoke concen-
trations can be kept constant while changes are made in the
concentration of nicotine delivered. This Section reviews these and
several other strategies used to investigate some form of tobac-
co/nicotine dose manipulation and the resultant effects on cigarette
smoking.

Control of Nicotine Intake

Among the most robust findings in research on cigarette smoking
is the stability of nicotine intake that occurs from day to day within
cigarette smokers. Several studies have collected blood samples from
cigarette smokers while they are smoking their own cigarettes
(Russell, Jarvis et al. 1980; Benowitz et al. 1983; Gori and Lynch
1985). This research has shown that blood levels of nicotine and
cotinine among different cigarette smokers are stable and are
relatively independent of the machine-estimated nicotine yield of the

158


cigarettes. Similarly, there are generally only modest correlations
between the number of cigarettes smoked per day and resultant
blood nicotine levels. This finding occurs because smokers consume
different amounts of nicotine from their cigarettes, according to how
the cigarettes are smoked. Figure 2 presents data from one of these
studies.

To explain why nicotine intake is not simply determined by the
machine-estimated nicotine yield of the cigarettes or the number of
cigarettes smoked, many other aspects of smoking have been
measured. This research is described in the remainder of this
Section.

Smoke Concentration

The concentration of tobacco smoke delivered to the lung can be
changed by dilution with air. Such dilution is an important means by
which the low smoking-machine-estimated ratings (e.g., Federal
Trade Commission ratings) of tar and nicotine are achieved in the so-
called "light" or "ultra light" cigarettes (Kozlowski 1981, 1982, 1986,
1987). One way to study the possible effects of smoke dilution is to
use the ventilated cigarette holders which have been marketed for
persons who are trying to quit smoking. In principle, the smoker
gradually reduces his or her level of dependence to nicotine by using
holders of gradually increasing ventilation level. Three laboratory
studies have evaluated the effects of such holders on cigarette
smoking behavior (Henningfield and Griffiths 1980; Sutton et al.
1978; Martin et al. 1980). The results of all three were consistent:
smoking was more intense at lower smoke concentrations and less
intense at the highest concentration. In fact, in one of the studies,
expired air CO levels were similar at all four concentration levels,
indicating that the changes in smoking intensity were sufficient to
defeat the holders' intended purpose of reducing the dose taken
(Henningfield and Griffiths 1980). Using a somewhat different
strategy, Zacny, Stitzer, and Yingling (1986) studied cigarette
smoking with commercially available ventilated cigarettes. When
the experimenter systematically blocked the filter vents of "ultra"
low-yield cigarettes, there were decreases in puffs per cigarette, puff
volume, and puff flow rate, and increases in interpuff interval.

These laboratory findings are consistent with findings obtained
outside the laboratory when the cigarette butts of vented cigarettes
are examined following smoking. Kozlowski, Rickert, Pope, and
Robinson (1982) found that the cigarette butts taken from people
who blocked the ventilation holes (often inadvertently) were more
stained by tar and nicotine, reflecting less effective dilution and
hence greater amounts of smoke delivery to the smoker. Data from a
laboratory study suggest that 40 percent or more of smokers may
inadvertently block the holes (Kozlowski, Rickert, Pope, Robinson,

159


  i-  1000
5                  0     o- 1 observation
P                  m-2 observations
  -  800 -
E                  a-3 observations
                     .
  .-
  i;j                    0-4 observations
               0      0
  E
8
A:       0
   0
iz
  .-
  .E
s
x
i

?   10  20  30  40  50  60  70 80 90 100
   Number of cigarettes/day

N= 137
r=0.15
NS

P
m   oir"
      
     0.0 0.2

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

. I

FTC nicotine yield (mg)

FIGURE 2.-Afternoon blood cotinine concentrations,
      compared by regression analysis with number
      of cigarettes smoked/day (A) and with U.S.
       Federal Trade Commission @TOdetermined
      nicotine yield (B)

NOTE: The grouped smokers' values (observations 2-A) were so similar to individual values that plots
overlapped Total number 01 subjects in B is lower because data for B few subjects were incomplete. Morning blood
cotinine concentrations (not shown) were on average slightly lower, but had similar correlations with number of
cigarettes Cr=0.45) and FTC yield (r=O.W.
SOURCE: Benowitz et al. (1983).

160


Frecker 1982). These findings imply that there is much greater
exposure to cigarette smoke in the general population than one
would expect based solely on the market share of ventilated
cigarettes (US DHHS 1981; Kozlowski 1987).

Cigarette Length

When cigarettes are shorter, people smoke more of them (Ashton,
Stepney, Thompson 1978; Goldfarb and Jarvik 1972; Gritz, Baer-
Weiss, Jarvik 1976; Jarvik et al. 1978; Chait and Griffiths 1982b).
Cigarette length may also affect how people smoke each cigarette.
Ashton, Stepney, and Thompson (1978) found that smokers short-
ened their intervals between puffs and spent a greater proportion of
time puffing on two-thirds-length cigarettes compared with full-
length cigarettes. Russell, Sutton, and associates (1980) reported that
smokers took relatively more puffs and left shorter butts when
smoking shortened cigarettes. In another study, subjects smoking
half-length cigarettes shortened the interval between puffs, but did
not spend more time puffing on these cigarettes relative to full-
length cigarettes (Chait and Griffiths 1982b). Puff duration and puff
volume were inversely proportional to the length of the tobacco rod,
even for the first puff of the cigarette (Chait and Griffiths 1982a;
Nemeth-Coslett and Griffiths 1984a,b, 1985).

Cigarette Brand

Numerous studies have examined the effects of cigarette brand
manipulations on cigarette smoking, and several reviews are avail-
able (Gritz 1980; Moss and Prue 1982; McMorrow and Foxx 1983).
Such studies are of practical importance because smokers often
switch to lower tar/nicotine yielding cigarette brands in an effort to
reduce this exposure to toxins and to reduce their level of nicotine
dependence (see Chapter VII). One finding of these studies is that the
number of cigarettes smoked per day is only slightly increased when
lower nicotine-yield brands are used. For this reason, it has been
suggested that smokers switch to lower yield cigarette brands (1) to
reduce exposure to smoke constituents and (2) to help them
gradually reduce their dependence on nicotine (see discussion of
these issues in US DHHS 1981 and in Chapter VII (nicotine fading)).
However, as discussed earlier, several other studies indicate that
there is little correlation between the nicotine rating of a cigarette
and the plasma nicotine level of the smoker (Russell, Jarvis et al.
1980; Benowitz et al. 1983; Gori and Lynch 1985). Kozlowski (1981,
1982) has observed that increases of only one or two puffs per
cigarette and possibly other more subtle changes in cigarette
smoking (e.g., blocking ventilation holes and taking deeper inhala-

161


tionst may defeat the intended purpose of the brand-switching
procedure.

Laboratory studies have provided information on the specific
changes in smoking behavior that may reduce the intended impact of
switching to lower yield brands of cigarettes. One confounding factor
in such studies is that machine-estimated nicotine, tar, and CO yields
do not necessarily change to the same degree or even in the same
direction from one cigarette brand to the next (Tobacco Reporter
1985); thus, no definitive conclusions can be drawn about which
specific smoke component was responsible for observed changes in
smoking behavior. Nonetheless, some orderly and consistent findings
emerge from a review of this literature. Several measures suggest
that when tobacco smoke constituent ratings decline, smoking is
more intense so that more smoke is delivered per cigarette;
conversely, when tobacco smoke constituent ratings are higher,
cigarette smoking becomes less intense (Frith 1971; Ashton, Stepney,
Thompson 1979; Stepney 1981; Guillerm and Radziszewski 1978;
Rawbone et al. 1978; Adams 1978; Creighton and Lewis 1978a; Ossip-
Klein, Epstein et al. 1983; Russell et al. 1982; Ashton and Watson
1970; Epstein et al. 1981; Russell, Epstein, Dickson 1983; Tobin and
Sackner 1982; Fagerstrom and Bates 1981; Woodman et al. 1987).

The consensus of the foregoing studies is that smokers tend to
smoke in ways that minimize the effect of attempted reductions in
nicotine intake; however, brand preferences can modulate nicotine
intake. One study employing biochemical measures of smoke intake
illustrated both of these phenomena (Benowitz and Jacob 1984).
Subjects were permitted t,o smoke under each of three cigarette
conditions: using their regular cigarette, using a higher nicotine-
yield brand, and using a lower nicotine-yield brand. Subjects
maintained significant nicotine intake under all three conditions,
but the highest intakes of nicotine were with the subject's preferred
brand. Nicotine intake from the lower nicotine-yield brands was
somewhat lower than intake from the higher yield brands. Taken
together, these studies indicate that brand switching may result in
somewhat decreased levels of intake of nicotine and other constitu-
ents of tobacco smoke. However, because of compensatory changes in
how cigarettes are smoked and in the number of cigarettes smoked,
the decreases are substantially less than would have been predicted
on the basis of the machine-estimated yield of the cigarettes.

Cigarette Yield of LVicotine

Research cigarettes which vary mainly in machine-estimated
nicotine yield ratings but little in the yield of other constituents (e.g.,
tar, CO) have also been used in laboratory and nonlaboratory studies
of cigarette smoking. This literature has been extensively reviewed
(Russell 1971, 1976; Gritz 1980; Henningfield 1984; US DHEW 1979;

162


US DHHS 1981). The consensus of the literature indicates that as
nicotine yield increases, the number of cigarettes smoked per day
tends to decrease, although the converse relationship is not as robust
(Russell 1979). Because few of these studies employed measures of
smoking other than number of cigarettes smoked per day, the degree
to which overall cigarette smoking behavior actually varied as a
function of such manipulations may have been underestimated
(Henningfield 1984).

Laboratory studies in which multiple behavioral measures of
cigarette smoking were employed indicate that smoking is sensitive
to nicotine dose manipulations. When cigarettes with higher nicotine
yield ratings are smoked, there are decreases in measures such as
puffs per cigarette, puff duration and puff volume, number of
cigarettes, and expired air CO; and increases in interpuff and
intercigarette interval (the specific measures were not identical for
the three studies summarized) (Herning et al. 1981; Gust and
Pickens 1982; McBride et al. 1984). These changes in smoking are
consistent with the interpretation that intensity of smoking is
inversely related to nicotine dose, indicating that compensatory
changes in smoking could be affected by nicotine itself.

Urine pH

Because some nicotine is normally eliminated in the urine,
manipulations of the rate of nicotine excretion might be expected to
change cigarette smoking behavior (see Chapter II). Rate of renal
excretion is partially determined by the acidity of the urine: lower
pH values (higher acidity) increase the rate of nicotine excretion.
One study showed that acidification of the urine of cigarette smokers
resulted in small increases in cigarettes smoked per day, and
alkalinization of urine was accompanied by only very small de-
creases in smoking (Schachter, Kozlowski, Silverstein 1977). A
subsequent study in which urine pH was varied showed no change in
cigarette smoking measures (Cherek, Mauroner, Brauchi 1982);
another showed small but significant effects on nicotine intake in
the expected direction (Benowitz and Jacob 1985).

The fact that there is a direct albeit weak relationship between
rate of nicotine excretion and cigarette smoking has suggested to
some that alkaline diets might be useful for persons trying to
decrease their cigarette smoking (Fix and Daughton 1981; Fix et al.
1983; Grunberg and Kozlowski 1986). However, the relatively small
amount of systemic nicotine which is eliminated by this route
(approximately 2 percent in alkaline urine, 10 percent in urine
without cont.rolled pH) (Rosenberg et al. 1980; Benowitz and Jacob
1985; Chapter II) weakens its practical significance as a determinant
of cigarette smoking behavior. The results of clinical studies suggest

163


that such therapies are not useful in the cessation of smoking (see
also Grunberg and Kozlowski 1986; Schwartz 1987).

Tobacco Administration and Deprivation

When tobacco smoke itself is given or withheld, the tendency to
smoke, as well as the way cigarettes are smoked, may be affected.
Kumar and colleagues (1977) reported that pretreating smokers with
a varying number of uniform puffs of tobacco smoke produced dose-
related reductions in the subsequent number of puffs taken, volume
per puff, and total puff volume during a 40-min period of smoking ad
libitum. In a study of similar design, Chait, Russ, and Griffiths (1985)
found that an increasing number of uniform pretreatment puffs
decreased subsequent puffs per cigarette, cigarette duration, and
total puff duration. Analogously, when the number of puffs available
during any period of smoking (smoking "bout") during a given day
was varied by the experimenter from 1 to 12 while the smokers were
free to vary the interbout interval, the intervals between each
smoking bout were directly related to the number of puffs that had
been given (Griffiths, Henningfield, Bigelow 1982). These studies
show that cigarette smoke intake is a function of time since the last
cigarette or the smoke dose given at any smoking opportunity.

Whereas smoke pretreatment decreases several measures of
cigarette smoke intake, other studies have found that deprivation for
just 1 hr increases the tendency to smoke and elevates several
measures of tobacco smoke intake (Henningfield and Griffiths 1979);
furthermore, these effects were not due to "anticipation" by the
subjects of the periods of smoke deprivation (Griffiths and Henning-
field 1982). Several additional studies have confirmed that smoke
deprivation increases one or more measures of cigarette smoking
(Karanci 1985; Griffiths and Henningfield 1982; Zacny and Stitzer
1985; Epstein et al. 1981). Sutton and coworkers (1982) found a small,
but statistically significant, positive correlation between time since
the last cigarette and total puff volume on the subsequent cigarette.
Similarily, when the interval between each smoking opportunity was
varied from 7.5 to 120 min and subjects were free to take as many
puffs per smoking bout as they pleased, the number of puffs per bout
was directly related to the duration of the preceding interbout
interval (Griffiths, Henningfield, Bigelow 1982). Restricting the
number of cigarettes that may be smoked is another way to study
tobacco deprivation. When smokers who on average smoked 37
cigarettes/day were permitted to smoke only 5 cigarettes/day, they
consumed three times as much nicotine per cigarette compared with
unrestricted smoking (Benowitz et al. 1986).

The results of studies of the effects of tobacco administration and
deprivation on subsequent rates and patterns of cigarette smoking
show that tobacco smoke can function as do other primary reinforc-

164


ers such as food, water, and dependence-producing drugs (Thompson
and Schuster 1964). Such studies in themselves, however, do not
reveal which of the many tobacco smoke constituents are critical.
The next two sections will examine evidence that specific manipula-
tions of nicotine and nicotine antagonists can produce analogous
changes in cigarette smoking.

Nicotine Pretreatments

One of the basic ways to demonstrate that a psychoactive drug is
controlling behavior is to determine if pretreatment with the drug
leads to decreases in the amount subsequently taken. Such findings
have been obtained with a variety of dependence-producing drugs
(e.g., Griffiths, Bigelow, Henningfield 1980; Chapter V), and the
strategy has been used to study the role of nicotine in cigarette
smoking. These studies have shown that nicotine pretreatment by a
variety of routes decreases the amount and/or intensity of subse-
quent cigarette smoking although the specific measures that have
been reportedly affected vary across studies. It is possible that
differences across studies reflect variations in sensitivity of measure-
ment techniques and in the measures used.

Cigarette smokers may be pretreated with nicotine by giving them
nicotine polacrilex gum to chew. The gum is available in similar
tasting nicotine dose levels of 2 or 4 mg/piece. A similar tasting
placebo preparation with no nicotine is also available. (In the United
States, the placebo and 4-mg dose are only available for research.)
With various combinations of nicotine gum doses it is possible to
provide a wide range of dose levels. In one study, the chewing of
nicotine polacrilex gum produced a dose-related (dose range = 0 to 8
mg nicotine) decrease in cigarette consumption during subsequent
90-min cigarette smoking sessions: Total puffs, total cigarettes, and
expired-air CO levels were inversely related to nicotine dose; desire
to smoke was also inversely related to dose but this effect varied
considerably and was not statistically reliable (Nemeth-Coslett et al.
1987). Comparable findings have been obtained in several other
studies, although dose manipulations were not as extensive as in the
former study (Kozlowski, Jarvik, Gritz 1975; Nemeth-Coslett and
Henningfield 1986; Brantmark, Ohlin, Westling 1973; Russell et al.
1976; Herning, Jones, Fischman 1985). Another study showed that
nicotine given in capsule form also reduced subsequent cigarette
smoking (Jarvik, Glick, Nakamura 19701, although the low dose and
poor systemic absorption of nicotine given by this route (see Chapter
II) required that much higher dose levels be given (10 mg).

Two studies have also demonstrated that intravenous (i.v.1 admin-
istration of nicotine decreases cigarette smoking (Lucchesi, Schuster,
Emley 1967; Henningfield, Miyasato, Jasinski 1983). Another study
found no change in smoking following iv. nicotine infusions (Kumar

165


et al. 1977); however, the dose (equivalent to about 1.7 mg, given in
10 divided doses over 10 min) was probably inadequate, as suggested
by results of other studies (Nemeth-Coslett et al. 1987). The finding
that even i.v.-delivered nicotine can reduce subsequent cigarette
smoking confirms that neither the tobacco vehicle nor the
oral/respiratory route is necessary for nicotine to control behavior.
The overall consistency of findings using a variety of forms of
nicotine pretreatment is evidence for a specific effect of nicotine as a
determinant of cigarette smoking.

Nicotine Antagonist Pretreatments

Another way to evaluate the specific role of nicotine as a
determinant of rate and pattern of cigarette smoking is to adminis-
ter drugs that block the effects of nicotine on the nervous system.
Nicotine antagonists (ganglionic blockers) are available as drugs
(e.g., pentolinium and hexamethoniuml that do not readily enter the
brain but are active in the peripheral nervous system, and as drugs
(e.g., mecamylamine) that do enter the brain and thus work in both
the peripheral and central nervous system (CNS) (Taylor 1985b). In
theory, such drug administ,ration should produce effects that are
analogous to those that would be expected if the nicotine dose of
cigarettes was decreased: that is, smoke intake should increase.
Moreover, if smoke intake increases, but only when the centrally
acting antagonist is given, such data would suggest the critical
involvement of the effects of nicotine in the brain.

Three studies showed that pretreatment of smokers with mecamyl-
amine produced increases in cigarette smoking that resembled those
expected if the nicotine dose of the cigarettes had been decreased
(Stolerman et al. 1973; Nemeth-Coslett et al. 1986a; Pomerleau,
Pomerleau, Majchrzak 1987). In each of these studies, the short-term
effect of the nicotine antagonists was studied. Similarly, mecamyl-
amine pretreatment increased the preference for high nicotine-yield
cigarette smoke (apparently by reducing its nicotinic effects) when
subjects were tested with a device which blends smoke from high and
low nicotine-yield cigarettes (Rose, Sampson, Henningfield 1985).
The role of nicotine action in the brain was demonstrated in the
study by Stolerman and colleagues (1973) in which a nicotine blocker
(pentolinium) that does not readily enter the brain produced no
effects on cigarette smoking.

Effects of Nonnicotinic Drugs on Cigarette Smoking

In addition to nicotine and nicotine antagonists, the effects of
other psychoactive drugs on cigarette smoking have been studied in
the laboratory. Such studies are important insofar as they constitute
drug-interaction studies whereby it may be determined if the

166


behavioral and physiological actions of nicotine are altered as a
function of pretreatment with other drugs. In addition, studies of
interactions of nicotine with other dependence-producing drugs are
important because tobacco use generally precedes and accompanies
use of many other dependence-producing drugs (Chapter V). Several
classes of psychoactive drugs have been administered in studies in
which cigarette smoking was specifically measured. In general, the
results permit a categorization of these drugs into two groups: (1)
those drugs that produce increases in smoking under standard test
conditions, and (2) those drugs that produce little reliable effect on
cigarette smoking under standard test conditions.

Sedatives, opioid agonists, and psychomotor stimulants have been
shown capable of producing robust and dose-related increases in
cigarette smoking. Specifically, alcohol (ethanol) has been shown t.o
increase cigarette smoke intake (Griffiths, Bigelow, Liebson 1976;
Henningfield, Chait, Griffiths 1984; Nil, Buzzi, Battig 1984; Mintz et
al. 1985; Mello et al. 198Ob). In a study in which alcohol was found to
increase smoking in all of five alcoholic subjects tested, pentobarbital
(a depressant) was found to increase smoking in the two subjects
with extensive histories of barbiturate use (Henningfield, Chait,
Griffiths 1984). The effects of alcohol and pentobarbital were most
robust in heavier drinkers and alcoholics (Henningfield, Chait.
Griffiths 1983, 1984). The opioid agonists, heroin and methadone,
increase cigarette smoking in opioid users (Mello et al. 1980a; Chait
and Griffiths 1984). Methadone produced dose-related increases in
number of cigarettes and puffs, and in puff duration in methadone-
maintained smokers (Chait and Griffiths 1984). Analogously, num-
ber of cigarettes smoked per day gradually decreased as methadone-
maintained clients had their daily methadone doses decreased over
several weeks (Bigelow et al. 1981). Finally, the psychomotor
stimulant d-amphetamine increases a variety of measures of ciga-
rette smoking (Henningfield and Griffiths 1981; Chait and Griffiths
1983).
Three other drugs have been studied and found to produce little
reliable effect on cigarette smoking. Caffeine is of interest because it
might be predicted to either increase smoking by its general
stimulant (amphetamine-like) effects (Rall 1985) or to decrease
smoking by serving as a substitute for some of nicotine's stimulant
effects (Kozlowski 1976). Laboratory studies, however, have found
the effects of caffeine administration on cigarette smoking to be
weak and inconsistent: two studies showed no reliable effect (Chait
and Griffiths 1983; Nil, Buzzi, Battig 1984), another showed weak
decreases in smoking (Kozlowski 1976), and a fourth showed weak
increases in smoking following caffeine administration (Ossip and
Epstein 19811.

167


The opioid antagonist naloxone (naloxone blocks effects of heroin-
like opioids) is another drug of interest because of the possible role of
endogenous opioids as mediators of some of the effects of nicotine
(Chapter III: Pomerleau and Pomerleau 1984). In a test paradigm in
which several drugs have been shown to produce orderly effects on
cigarette smoking (Griffiths and Henningfield 1982), naloxone
produced no consistent changes in cigarette smoking over a wide
range of dose levels (Nemeth-Coslett and Griffiths 1986). Another
study of the effect of naloxone which employed a single dose found a
reduction in smoking (Karras and Kane 1980). No clear reconcilia-
tion of these disparate findings is evident. Finally, marijuana
pretreatment was found to produce no reliable effect on tobacco
intake (Mello et al. 1980b; Nemeth-Coslett et al. 1986b) or on the way
cigarettes were smoked (Nemeth-Coslett et al. 1986b).

Effects of Nonnicotine Constituents of Tobacco Smoke and
Citric Acid Aerosol

Chemicals presumed to act primarily in the respiratory tract and
not in the central nervous system may also affect smoking. The
region of the trachea just below the larynx is assumed to be a site of
some cigarette smoke related sensations (Cain 1980). This site
corresponds to the region 2 cm below the narrow opening of the
larynx where particles entering the trachea change direction (Chan
and Schreck 1980).

The components of cigarette tar and volatile gases in smoke
contribute to the taste, olfactory, and tracheobronchial sensations
elicited by cigarette smoke. In fact, minimal levels of tar are held by
tobacco manufacturers to be important to maintain product satisfac-
tion in smokers (Tobacco Reporter 1985; Gori 1980). Besides its
causal role in lung cancer and other diseases (US DHHS 1982, 1983,
1984), tar may function to mask the harshness and irritation of
nicotine (Herskovic, Rose, Jarvik 1986). Consistent with this hypoth-
esis, nicotine aerosols delivering doses of nicotine similar to those in
mainstream cigarette smoke are rated as extremely harsh and
irritating by cigaret,te smokers (Russell 1986). Similarly, some
gaseous components of smoke, such as acrolein and formaldehyde,
are irritating and could also contribute to the tracheobronchial
sensations elicited by smoke (Lundberg et al. 1983).

Levels of tar and other constituents may also contribute to brand
preference and, conversely, to the difficulty in finding readily
acceptable substitutes for the cigarettes normally smoked by individ-
uals. For example, a nonmentholated cigarette may not be a
desirable substitute for a mentholated one. Moreover, when given
cigarettes made of lettuce or cocoa leaves, smokers complain about
the unpleasant smell and taste (Goldfarb, Jarvik, Glick 1970;
Herskovic, Rose, Jarvik 1986). Tobacco research cigarettes are often

168


found to be less palatable than commercial brands (Benowitz, Kuyt,
Jacob 1982), indicating the importance of specific tobacco blends
and/or additives in determining taste and brand preferences.

The precise nature of the sensations critical to smoking satisfac-
tion has not been elucidated, and the relative roles of taste, olfaction,
and tracheobronchial sensations are not clear. One way to assess the
importance of local respiratory sensations in the subjective response
to cigarette smoke is to block these sensations with a short-acting
topical anesthetic. Two studies have used inhalation of a 4-percent
lidocaine aerosol and mouth rinses and gargling with lidocaine
solutions to assess the importance of airway sensations to cigarette
smokers (Rose et al. 1984, 1985). In both studies, the desirability of
puffs was decreased by local anesthesia of the respiratory tract.
Additionally, the decline in reported craving for cigarettes that
usually occurs after smoking was diminished by local anesthesia.

A study was also conducted in which smokers inhaled a refined
tobacco smoke condensate (Rose and Behm, in press). The condensate
produced a low overall nicotine yield (about 0.2 mg,`lO puffs), while
maintaining a higher ratio of nicotine to tar and a larger particle
size than that of conventional cigarette smoke. Smoke generated in
this fashion was rated as stronger and harsher than smoke of
equivalent nicotine content delivered by smoking a conventional
low-tar and low-nicotine cigarette (Rose and Behm 1987). The
subjects also reported significantly greater satisfaction and dimin-
ished desire to smoke additional cigarettes after inhaling puffs of
refined smoke compared with conventional low-nicotine cigarette
smoke (Rose and Behm 1987). These studies demonstrate that local
sensory effects of smoke may influence the short-term subjective
responses to smoking.

The inhalation of aerosols containing citric acid is a standard
method of eliciting coughing in human subjects (Pounsford and
Saunders 1985). One study found that smokers inhaling puffs of a
nebulized 15 percent aqueous solution of citric acid reported
sensations of strength and harshness comparable to those produced
by their own cigarette brand and considerably stronger than those
elicited by an "ultra" low-tar, low-nicotine cigarette (Rose and
Hickman 1987). Moreover, some pleasure was reported to be
associated with these sensations, and desire for cigarettes was
decreased, suggesting that mild irritation of the respiratory airways
may be involved in satiation of smoking behavior and may have a
role in smoking cessation efforts (Henningfield 1987c; Chapter VII).

Nicotine: Psychoactivity, ReinforcIng and Related Behavioral
Mechanisms of Nicotine Dependence
As the preceding sections have shown, cigarette smoking is an
orderly behavioral and pharmacologic process clearly involving

169


maintenance of the desired levels of nicotine in the body. These data
are sufficient to label tobacco use as a form of drug self-administra-
tion in which the role of nicotine in controlling tobacco self-
administration functions as do morphine, ethanol, and cocaine in the
use of opium-derived products, alcoholic beverages, and coca-derived
products, respectively. However, the question may be asked whether
the behavior-controlling pharmacologic properties of nicotine are
similar to those of prototypic dependence-producing drugs when
evaluated in standard laboratory tests. More specifically, the scien-
tific question is whether nicotine itself shares critical dependence-
producing properties with drugs such as morphine, cocaine, and
alcohol. Standardized testing procedures can be used in both animal
and human studies to objectively determine if a drug is dependence
producing. These procedures, as well as a review of how addicting
drugs control behavior, is presented in Chapter V. Chapter V also
presents data obtained when drugs such as morphine, cocaine, and
alcohol are tested by identical procedures.

In brief, four general kinds of behavior-modifying drug effects can
be differentiated on the basis of the test procedure used. These drug
effects are discussed in Chapter V and include the following: (1)
Drugs may produce interoceptive stimulus effects; that is, they can
produce effects that a person or animal can distinguish from the
nondrug state. Although not identical in meaning, the following
terms are often used to designate interoceptive drug effects: "psy-
choactive, " "discriminative," "subjective," "self-reported." (2) Drugs
may serve as positive reinforcers or rewards, the presentation of
which produces repetition and strengthening of the behaviors which
led to their presentation, i.e., "drug self-administration" or "drug
seeking." (3) Drugs can serve as unconditioned stimuli, in which case
they may directly elicit various responses; these responses may
subsequently be elicited by stimuli which are associated with the
drug (i.e., conditioned stimuli), including the presence of environ-
mental, or even internal, cues. (4) Drug administration or abstinence
can also function as "punishers" or aversive stimuli.

This Section will present data from studies of nicotine with each of
the four testing procedures mentioned above. The convergence of
findings from several distinct approaches provides compelling evi-
dence that nicotine is a drug that can effectively control behavior,
including behavior leading to its own ingestion (i.e., dependence or
addiction).

Interoceptive, Discriminative, and Subjective Effects of
Nicotine

Ingested chemicals can serve as stimuli by actions on either
peripheral or centrally located receptors or by indirect effects
mediated through the release of various biochemicals or neurohor-

170


mones. In general, the term "psychoactive" is reserved for those
drugs whose discriminative effects are known to result from their
actions in the brain. As described by Lewin (1931) and others
(Thompson and Unna 1977) it is, in part, the nature of the
discriminative stimulus effects of a drug within the body that sets
the dependence-producing drugs apart from other non-nutritive
substances. As shown in Chapter II, all commonly used forms of
tobacco are effective means of delivering nicotine to the blood from
which it is rapidly transported to the brain. Research with animals
has shown that nicotine produces distinct effects in the central
nervous system (CNS). In addition, nicotine has diverse peripheral
and hormonal actions that could serve to intensify its CNS stimulus
properties. The biochemical mechanisms of these effects are discuss-
ed in Chapter III.

Three procedurally distinct methods have been used to character-
ize the stimulus properties of nicotine and will be discussed in the
following sequence: (1) discrimination testing in animals and hu-
mans, (2) assessing subjective effects in humans, and (3) testing for
state-dependent learning effects in humans. Each method has been
used to help characterize the stimulus properties of a variety of
drugs including nicotine (Chapter V).

Drug Discrimination Testing in Animals

Animal studies of nicotine discrimination show that nicotine
produces reliable effects that are readily identified by the subjects.
Such studies indicate that fundamental biobehavioral mechanisms
mediate the psychoactive properties of nicotine in humans, and that
such effects are not unique to human psychological processes. These
data also have implications for understanding and treating tobacco
dependence and are summarized below.

Specificity of the Nicotine Stimulus

Although dependence-producing drugs may overlap, to some
degree, in the nature of their effects on mood and feeling, each drug
class and sometimes drugs within *a class produce unique effects. As
this Section shows, nicotine also produces some effects that permit it
to be distinguished from most other psychoactive drugs. These
studies are also useful for testing new drugs that are thought to
produce nicotine-like effects.

Rats can learn to accurately discriminate nicotine from placebo
regardless of the route of administration as long as the nicotine
reaches the brain. Most researchers have utilized the subcutaneous
(s.c.) route of administration iRosecrans and Meltzer 1981); however,
more recent studies have incorporated other routes of nicotine
administration and have found that rats could learn to discriminate

171


nicotine when given nicotine by gavage (oral tube) in a dose of 0.5
mg/kg (Howard and Craft 1987). Oral nicotine-trained rats general-
ized to nicotine administered via either the S.C. or transdermal
routes (nicotine solution was applied to a 1.5cm circular area on the
shaved back of the rat). There was little difference in dose potency
between the oral and S.C. routes; however, the transdermal route was
much less potent and required eight times the oral dose to establish
equivalent response patterns. Taken together, the results of these
studies showed that nicotine given by a variety of routes produces
time- and dose-related discriminative effects.

Several studies have compared nicotine with a variety of drugs by
these drug discrimination testing procedures (Rosecrans and Meltzer
1981; Stolerman et al. 1987). Early research involved testing a wide
variety of chemicals. These studies showed that nicotine-trained rats
did not generalize to drugs of other classes such as the opioids,
barbiturates, or hallucinogens (Rosecrans and Meltzer 1981). Of
special interest was the prototypical stimulant d-amphetamine,
because nicotine also has a variety of stimulant-like actions (Rall
1985). When nicotine-trained rats were tested with amphetamine,
however, they only partially generalized to nicotine. In another
study, Schechter (1981) observed higher levels of amphetamine
generalization to nicotine in a group of rats trained to discriminate
amphetamine from pentobarbital. Thus, nicotine may have some
amphetamine-like effects which are unmasked under certain condi-
tions.

Oxotremorine and arecoline are agonists of the cholinergic ner-
vous system, but these drugs activate muscarinic, and not nicotinic,
cholinergic receptors (Gilman et al. 1985). Consistent with the
mechanisms of action of these cholinergic drugs are the findings that
neither oxotremorine nor arecoline generalized to nicotine in
nicotine-trained animals (Rosecrans and Meltzer 1981).

Nicotine analogs and metabolites have also been studied with the
discrimination paradigm (Rosecrans and Chance 1977; Stolerman et
al. 1987). Such research can help reveal the extent, if any, of the role
of these nicotine-related or nicotine-derived chemicals in determin-
ing the nature of the discriminative effects that follow nicotine
administration. In rats trained to discriminate 100 pgf kg of nicotine,
the analogs cytisine and anabasine generalized to nicotine. The
alkaloid nornicotine generalized partially to nicotine. Cotinine, the
major metabolite of nicotine, was observed to generalize to nicotine
only when the cotinine was given intraventricularly in relatively
high doses to rats trained to discriminate relatively low dose levels
(100 pg/kg) of nicotine. These data show that although metabolites of
nicotine may share some stimulus properties with nicotine, the
degree of generalization is weak, suggesting that the discriminative

172


stimulus effects of nicotine are mainly due to nicotine itself and not
to the metabolites.

Synthetic analogs of nicotine have also been evaluated for their
possible nicotine-like properties in discrimination studies (Rose-
crans, Kallman, Glennon 1978; Rosecrans et al. 1978). Of the several
compounds tested, only one, 3-methyl-pyridylpyrollidine, a chemical
isomer of nicotine, was observed to generalize to the nicotine
stimulus in nicotine-trained rats. This compound was observed to be
8 to 10 times less potent than nicotine. Its effects were significantly
antagonized (reduced or blocked) by mecamylamine, which also
antagonizes the stimulus generated by both S- and R-nicotine; the
naturally occurring tobacco constituent, S-nicotine, is also 8 to 10
times more potent as a stimulus than R-nicotine. The results of
these investigations indicate that the stimulus properties of nicotine
are highly specific.

A finding relevant to pharmacologic treatment efforts (see Chap-
ter VII) involved discrimination studies with lobeline (a constituent
in several over-the-counter aids for quitting smoking). Lobeline is an
alkaloid with some nicotine-like ganglionic effects in the peripheral
nervous system (Gilman et al. 1985). Rosecrans and Chance (1977)
found that lobeline was neither discriminated as nicotine nor did it
block nicotine discrimination in nicotine-trained rats. These results
do not support the use of lobeline-containing compounds as treat-
ment aids for cigarette smoking (see also Schwartz 1987; Chapter
VII).

Peripheral Versus Central Discriminative Stimulus Effects of
Nicotine

The degree to which the stimulus is generated via peripheral
rather than central nervous system (CNS or brain) actions is also
important in understanding the nature of the nicotine stimulus. As
discussed in Chapter III, nicotine has many peripheral autonomic
nervous system CANS) effects which might feed back to the CNS,
thereby indirectly generating or contributing to stimulus effects.
Thus, changes in blood pressure, heart rate, body temperature, and
hormone release could be potential mediators of the effects. Several
approaches have been utilized to address the role of peripheral
actions of nicotine in the generation of the discriminative stimulus.
One approach is to attempt to block nicotine with an antagonist not
able to enter the CNS.

In one study, animals were trained to discriminate a dose of
nicotine (Rosecrans and Chance 19771. Then they were pretreated
with a series of nicotinic cholinergic antagonists and with muscarin-
ic cholinergic antagonists. After pretreatment with an antagonist,
the animals were retested with the training dose of nicotine.
Mecamylamine, a centrally and peripherally acting nicotine antago-

173


nist, was the only drug observed to completely block the nicotine
stimulus. As the dose of this antagonist was increased, percent
correct responses on the nicotine-correct lever, after the injection of
200 or 400 pg/kg of nicotine, decreased to placebo response levels,
indicating a complete antagonism of the nicotine stimulus. In a
similar study, Stolerman, Pratt, and Garcha (1982) increased the
nicotine dose in an attempt to overcome the actions of mecamyla-
mine: the blockade was not overcome by any dose of nicotine. Thus,
these data suggest that mecamylamine is not a competitive antago-
nist (blocking at the receptor itself) but rather may functionally
antagonize nicotine's effects through another mechanism (Stolerman
et al. 1987).

In other studies, a 331 ug/kg dose of mecamylamine antagonized
the stimulus effects of 200 pg/kg of nicotine, while 835 ug/kg was
required for similar antagonism of the 400 ug/kg dose of nicotine
(Rosecrans and Meltzer 1981). All such studies found that the
peripherally acting nicotinic antagonist, hexamethonium, did not
affect nicotine discriminations. The muscarinic antagonist, atropine,
was also without effect. The possible relationships of the nicotine
stimulus to brain norepinephrine and 5-hydroxytryptamine (seroto-
nin or 5-HT) systems were also investigated through the use of the
appropriate antagonists/agonists. Similarly, a quaternary analog of
nicotine, which does not enter the brain, was evaluated and found to
produce no evidence of generalization in nicotine-trained rats
(Rosecrans et al. 1978). Such studies do not support the involvement
of peripheral systems in the generation of the nicotine stimulus.

Another strategy used to investigate the central nature of the
nicotine stimulus compared concentrations of nicotine in the brain
with the resulting stimulus effects of nicotine (Rosecrans and Chance
1977). It was assumed that if nicotine's stimulus effects are mediated
in the brain, then such effects should be related to brain levels of
nicotine. This hypothesis was confirmed. In fact, it was found that
before nicotine functions as a stimulus, it must achieve a minimal
drug level in the brain. In addition to relating drug level in the brain
to the stimulus effect induced by nicotine, Rosecrans and Chance
(1977) showed that systemically administered :lico%ine generalized to
nicotine administered intraventricularly. Taken together, the fore-
going studies show that the nicotine-generated discriminative stimu-
lus is dependent on the actions of nicotine at central nicotine
receptors in the brain.

Drug discrimination research has also examined the stimulus
properties of the muscarinic cholinergic agonist, arecoline. Arecoline
is a constituent of the betel nut mixtures commonly chewed in the
East Indies (Taylor 1985al. Three approaches have been utilized to
investigate the stimulus properties of arecoline. In the first study,
arecoline served as a discriminative stimulus and thereby assumed

174


control of behavior (Rosecrans and Meltzer 19811. These effects of
arecoline were blocked by pretreatment with the muscarinic antago-
nist, atropine, while the quaternary compound, methyl atropine
(which does not readily cross the blood-brain barrier), was ineffec-
tive. These results indicate that the stimulus can also be exerted via
muscarinic stimulation and confirm that the discriminative stimulus
properties of muscarinic agonists. like those of nicotinic agonists, are
centrally mediated. Additional studies indicated that mecamylamine
was not able to antagonize the stimulus effects of arecoline (Rose-
crans and Meltzer 1981). Finally, it was found ihat rats could be
trained to discriminate between the muscarinic and nicotinic
agonists, arecoline and nicotine. Thus, there appear to be two
independent central cholinergic recept,or systems (muscarinic and
nicotinic), each of which can exert stimulus control over behavior
when appropriately stimulated. These findings have been confirmed
by Stolerman and colleagues (1987).

Interactions with Noncholinergic Neurons

In a preliminary study (Takada et al., 1988) two nic;)tine-trained
squirrel monkeys recognized beta-carboline as nicotine. Beta-carbo-
line induces symptoms resembling anxiety in animals; these symp-
toms can be reduced by administration of the anxiolytic, diazepam
(Shephard 1986). In addition to this observation, Colpaert (19771
reported that nicotine can antagonize the diazepam cue, and Heath,
Porter, and Rosecrans (1985) noted that nicotine antagonized the
effects of diazepam on punished responding in rats. Mecamylamine
was also found to attenuate the nicotine-induced antagonism of
diazepam's antianxiety effect. Harris and coworkers (1986) found
that metrazol (a convulsant) partially generalized (35 percent) to
nicotine when tested in the discrimination paradigm in nicotine-
trained animals. A greater degree of generalization of the metrazol
cue to nicotine (50 percent) was observed 48 hr after the cessation of
a 21-day chronic nicotine regimen in rats trained to discriminate
metrazol (5 mg/kg) from saline; these generalizations were not
antagonized by mecamylamine. Harris and colleagues (1986) suggest-
ed that the generalization of metrazol to nicotine was a function of a
nicotine abstinence-induced withdrawal syndrome resembling anxie-
ty. These studies suggest that nicotine may act, at central receptors
capable of eliciting a stimulus cluster which induces anxiety
(Chapter III).

Subjective Effects of Nicotine in Humans
The extensive amount of nicotine discrimination research using a
variety of animal species and several routes of administration
confirms that nicotine is a potent drug that can induce alterations in

175


nervous system function that are distinct and readily identifiable. In
addition, the similar findings observed in studies using different
routes of nicotine administration are consistent with the hypothesis
that the tobacco vehicle is not necessary to produce nicotine-associ-
ated changes of mood and feeling. The next Section examines data
from analogous studies in which humans served as research subjects.

Psychoactivity of Nicotine

The animal research described above indicates that nicotine's
psychoactivity is a result of basic biological actions. Human research
on nicotine corroborates the validity of the animal research. Results
from studies of the interoceptive effects of nicotine in humans are
analogous to those obtained in animal studies described above.

One of the first human studies that used drug discrimination
procedures, as had been developed with animal subjects, was a study
of nicotine discrimination. The study involved the systematic
manipulation of nicotine dose levels with research cigarettes which
varied primarily in the amount of nicotine delivered (Kallman et al.
1982). This study demonstrated that nicotine, as delivered by the
inhalation of tobacco smoke, produces discriminative stimulus
effects. The degree and rate of acquisition of the discrimination
appeared to be dose dependent. The ability of the subjects to make
the discriminations did not appear to be related to either autonomic
(e.g., heart rate) effects of nicotine or to nicotine's effects on other
self-reported measures (e.g., taste of the cigarette).

The data from Kallman and associates (1982) are consistent with
those of several other studies which have found that human
volunteers can differentiate among cigarettes which vary mainly in
the amount of nicotine which they deliver (Goldfarb, Jarvik, Glick
1970; Goldfarb et al. 19'76; Herskovic, Rose, Jarvik 1986; Rose 1984;
Griffiths, Bigelow, Henningfield 1980; Henningfield, Miyasato, John-
son, Jasinski 1985). Furthermore, the conclusion that centrally
mediated effects of nicotine are important in such responsivity is
supported by findings that pretreatment with mecamylamine re-
duced responsivity to nicotine dose levels of the cigarette (Stolerman
et al. 1973; Nemeth-Coslett et al. 1986a; Pomerleau et al. 1987). The
study by Stolerman and associates (1973) also showed that such
antagonism of nicotine's effects was not obtained when peripherally
acting pentolinium was given.

Other research has confirmed that the tobacco vehicle is not
necessary to enable the interoceptive effects of nicotine. Several
studies involving i.v. administration of nicotine in human subjects
have found that humans readily differentiate among nicotine dose
levels given intravenously. In the earliest of these studies, i.v.
injections of nicotine were given to 35 volunteers, most of whom
were cigarette smokers (Johnston 1942). The conclusions of Johnston

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TABLE 3.-Summary of early observations regarding
      psychoactivity of intravenously delivered
       nicotine in humans

1.

"Psychic" effects are directly related to nicotine dose; nonsmokers are
much more sensitive to toxic symptoms ieg., nausea) than smokers

2.

Effect of nicotine is "specific and readily distinguished from that of
cocaine or codeine"'

3.

Nicotine injections are "pleasant" to smokers, and are preferred by some
over cigarette smoking

4.

Orally given nicotine (dissolved in water) also had "psychic" action. but
appeared much less potent than intravenously administered nicotine:
delayed onset of effect

5. - l-3 mg doses appeared tolerable and equivalent to smoking single
   cigarette; - 0.11 mg doses appeared to produce "subjective sensation"
   equivalent to one "deep" cigarette smoke inhalation

`More recent research indm&s that higher dose levels of mcotine can produce cocainelike effects
(Henning&Id. Miyasato. Jasinski 1985).
SOURCE: Johnston (1942).

that are especially relevant to characterization of the psychoactivity
of nicotine are shown in Table 3.

Johnston's findings (Table 3) have been generally confirmed.
Jones, Farrell, and Herning (1978) and Rosenberg and colleagues
(1980) also found that human volunteers could differentiate i.v.
nicotine at dose levels similar to those obtained by smoking
cigarettes. In another study which extended the findings of Johnston
(1942), both i.v. nicotine and nicotine inhaled from research ciga-
rettes across a range of doses were administered to human volun-
teers with histories of using a variety of dependence-producing drugs
(Henningfield, Miyasato, Jasinski 1985). Subjects clearly distin-
guished nicotine from a placebo, and the dose strength estimates
were directly related to the nicotine dose level. A subsequent study
showed that the immediate subjective effects of nicotine were
diminished by pretreatment of subjects with mecamylamine (Hen-
ningfield et al. 1983).

In a study by Henningfield, Miyasato, Jasinski (1985), measures
used to qualitatively describe the nature of the drug stimulus
indicated that nicotine met criteria as a euphoriant. At higher doses
nicotine was sometimes identified as a stimulant (cocaine or
amphetamine); it elevated scores on the Morphine Benzedrine Group
("Euphoria" or "MBG") scale of the Addiction Research Center
Inventory (ARCI) (Haertzen and Hickey 1987); and it produced dose-
related increases in scores on a drug-liking scale. The high-dose
cocaine/amphetamine identifications found in the study by Hen-
ningfield, Miyasato, and Jasinski (1985) were not observed by

177


Johnston, but such similarities between nicotine and cocaine may
only be clearly identifiable by subjects experienced with both cocaine
and nicotine.

Nicotine given in the polacrilex gum form has been evaluated with
similar measures as described above. These studies involved giving
various combinations of 2-mg- and 4-mg-nicotine pieces of polacrilex
gum and placebo to cigarette smokers. Human volunteers were given
the polacrilex gum to chew in doses ranging from 0 to 4 mg in one
study [~Nemeth-Coslett and Henningfield 1986) and 0 to 8 mg in
another study (Nemeth-Coslett et al. 1987). Both studies showed that
subject ratings of several effects (including "dose strength") were
directly related to the total dose of nicotine that was given. In
addition, similarity of the stimulus effects to those produced by
cigarettes was a direct function of dose level. In these studies
"liking" or "positive" effect scores were inversely related to dose
level, suggesting that this nicotine delivery system has low potential
for causing dependence when compared with that of cigarettes
(Chapter VII). The role of centrally mediated nicotinic actions in the
ability of humans to differentiate among polacrilex gum-delivered
nicotine doses was confirmed in a study by Pickworth, Herning, and
Henningfield (in press). These researchers found that mecamyla-
mine pretreatment of human volunteers reduced both the EEG and
subjective effects of nicotine polacrilex gum administration.

Like many other psychoactive drugs (Chapter V), nicotine can also
produce unpleasant or dysphoric subjective effects that are related to
the dose given and the route of administration. Such effects can be
quantified by a psychological scale of the ARCI that is sometimes
referred to as the "dysphoria" scale (Jasinski, Johnson, Henningfield
1984) or the "LSD" scale because ii: was constructed from items
found to be elevated when lysergic acid diethylamide (LSD) was
given to volunteers (Haertzen 1966, 1974).

In one study, Henningfield, Miyasato, and Jasinski (1985) found
that both inhaled (research cigarette smoke) and i.v. nicotine
produced dose-related increases in LSD scale scores. In two other
studies, nicotine polacrilex gum was tested (Nemeth-Coslett and
Henningfield 1986; Nemeth-Coslett et al. 1987). LSD scale scores
were at least slightly increased in both studies and were significantly
increased in the study by Nemeth-Coslett and Henningfield (1986).
These results with nicotine polacrilex gum, combined with no
increases in MBG scale scores, are consistent with the observations
described earlier suggesting a low overall dependence potential for
this formulation.

Sensory Effects of Nicotine

As discussed earlier in this Chapter, nonnicotine constituents of
tobacco smoke can produce functional sensory effects. Nicotine, too,

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can produce peripherally mediated sensory effects which could
contribute to the taste of the cigarette. Although not generally
termed "psychoactive" drug effects, such effects could contribute to
the control over behavior as they provide discrete cues which may be
associated with centrally mediated nicotinic effects. For example,
nicotine has a bitter taste, elicits burning sensations when placed on
the tongue, and is irritating to the oral and respiratory mucosa
(Windholz et al. 1976). Increasing the nicotine delivery of cigarettes
while holding tar delivery constant leads to an increase in perceived
strength and harshness. The possible effects of nicotine in the upper
respiratory tract on subject ratings cannot be excluded in these
studies. Nicotine also stimulates mechanoreceptors sensitive to
pressure and stretch (Taylor 1985b), and this local action of nicotine
may also contribute to the sensory characteristics of inhaled
cigarette smoke.

Hexamethonium (the nicotine receptor antagonist that only acts
peripherally) has been shown to block cigarette smoke-induced
edema in the tracheobronchial mucosa of rats (Lundberg, Saria,
Martling 1982). Another study showed that mecamylamine produced
dose-related decreases in harshness ratings of individual puffs of
cigarette smoke (Rose, Sampson, Henningfield 1985). In this study,
subjects were asked to rate their preference at different nicotine
concentrations of the smoke: mecamylamine pretreatment shifted
preferences to higher smoke concentrations for individual puffs.

Another method of producing at least some of the nicotine-related
sensations of cigarette smoke is to present nicotine in vapor or
aerosol form without any components of tar. Nicotine vapor is likely
to be deposited mainly in the mouth and pharynx (Russell 1986);
thus it. would be difficult to administer a pharmacologically effective
dose of nicotine without producing excessive local irritation and bad
taste. However, a low dose of nicotine delivered in this fashion might
simulate the sensory effects of smoking, even if the pharmacologic
effects are minimal. A low-dose nicotine aerosol delivering droplets 1
to 5 pm in size would be expected to provide respiratory sensations
even more similar to cigarette smoking, as particles of this size
would impact mainly in the tracheobronchial region.

Three studies have evaluated the effects of a commercially
marketed nicotine vapor delivery system in human subjects. The
delivery system was a version of that originally described by
Jacobson, Jacobson, and Ray (1979); it was marketed as a "tobacco
product" through February 1987, when the Food and Drug Adminis-
tration (FDA) required verification of "safety and efficacy" for
continued marketing as a "nicotine delivery system" (see Chapter
VII). It consisted of a cigarette-size plastic tube with a nicotine-
containing polymer in the end distal from the user's mouth. It was
used by sucking air through the tube and inhaling in a manner

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similar to that when smoking cigarettes. When the system was used
in this fashion, two studies found that plasma nicotine levels were
not significantly elevated (Sepkovic et al. 1986; Henningfield 1986b).
A third study found significant elevations in plasma nicotine
following use of the nicotine tube (Russell et al. 1987). However, in
the latter study subjects used what may be described as a heroic
puffing procedure: they were instructed to puff 1 nicotine tube 10
times, at intervals of 40 set; after a 4-min pause, subjects then
"puffed and inhaled as hard and as frequently as possible, continous-
ly for the next 20 min, with changes every 5 min to fresh cigarette
[nicotine tube]." Symptoms typical of those associated with higher
levels of nicotine administration were observed, i.e., dizziness,
lightheadedness, and in a few subjects, nausea (Russell et al. 1987).

In another study of the nicotine vapor inhaler, four tubes in which
none, one, two, or four contained nicotine (the others being denico-
tinized) were simultaneously puffed on by volunteers through a
specially designed cigarette holder (Henningfield 198613, 1987a). In
this study, despite the fact that measurable changes in plasma
nicotine levels did not occur, several responses often associated with
nicotine delivery were observed: (1) subject ratings of "harshness"
were directly related to dose (number of nicotine-containing tubes);
(2) post-puffing increases in heart rate occurred as a function of dose;
(3) subjective effects were directly related to dose; and (4) desire to
smoke tobacco cigarettes was inversely related to nicotine dose level.
Taken together, these results show than even with negligible
systemic levels, nicotine can induce feelings of satisfaction and can
reduce urges to smoke when it produces tobacco-like sensations of
throat burn and harshness (Chapter VII).

Some of the short-term satisfaction derived from inhaling nicotine
may explain the apparent short-term efficacy of the vapor inhaler in
reducing desire to smoke despite negligible plasma nicotine levels.
This is in contrast to findings obtained when nicotine is given either
intravenously or in the polacrilex gum (Henningfield, Miyasato,
Jasinski 1983; Nemeth-Coslett et al. 1987). Whether the effects of the
nicotine vapor inhaler are conditioned responses, peripheral nicotin-
ic actions, or both, it remains to be determined if such effects would
provide long-term efficacy as tobacco replacement in the nicotine-
dependent tobacco user (Chapter VII). Such effects may not be
satisfactory for long-term tre