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