Neurotransmitters are hormones that are stored in nerve endings or terminals located in the brain. When neurotransmitters are released from nerve endings, they cross the synapse (the space between nerves) and send chemical messages from the brain across nerve channels. Receptor molecules in the post-synaptic (receiving) nerve endings recognize pre-synaptic (sending) neurotransmitters. These receptors are specially shaped to receive the appropriate neurotransmitters, which fit in the receptor like a key in a lock. Epinephrine (also known as adrenaline) and its chemical cousin, norepinephrine (also called noradrenaline), are members of a class of hormones called the catecholamines, which function as neurotransmitters in the sympathetic nervous system.
Axelrod's interest in neurotransmitters was galvanized by two factors. One was the physiological effect of the sympathomimetic amines on neurotransmitters, and on the behavior of organisms in general. The second was the emergence of a new class of controlled medications, such as chlorpromazine and Ritalin, which were used by clinical psychiatrists to control violent and psychotic behavior in their patients. Axelrod turned his attention away from drugs that induced altered states of consciousness, such as LSD-25, and toward this new class of drugs used to regulate schizophrenic and depressed states associated with mental illness.
Axelrod was not the first laboratory researcher to attempt to find causal links between drug metabolism and mental health. In 1948, Seymour Kety, a former NIMH scientist often acknowledged as the "father" of modern biological psychiatry, compared rates of oxygen flow and energy metabolism in both schizophrenic and non-schizophrenic patients but found no difference. In 1952, Humphrey Osmond and Abraham Hoffer of the University of Saskatchewan saw that niacin (Vitamin B-3) helped relieve symptoms of schizophrenia in their patients. Osmond and Hoffer also suggested that mental illness might be caused by an imbalance of the hormone adrenaline. Linus Pauling, the polymath scientist and intellectual who won the 1954 Nobel Prize in Chemistry, termed vitamin therapy "orthomolecular psychiatry."
In 1956, Kety presented the findings of Osmond and Hoffer at a NIMH seminar and piqued Axelrod's curiosity. In 1957, Axelrod studied enzymes released from nerve endings along with the neurotransmitter norepinephrine. One of these was the enzyme monoamine oxidase (also called MAO). Since the early 1950s scientists had found MAO to intercept the action of neurotransmitters, and had developed a class of antidepressant drugs known as monoamine oxidase inhibitors (MAOIs) that disable the enzyme and allow neurotransmitters to work properly. Like many scientists of the period, Axelrod initially believed that these enzymes disengaged the neurotransmitter once it reached the post-synaptic terminal. Axelrod, however, disproved this theory in 1959 when he conducted a series of experiments to understand the distribution of norepinephrine in the tissues of cats. Axelrod concluded that the MAO enzyme does not deactivate neurotransmitters but in fact helps to increase catecholamine levels in the nerve terminal.
By 1961, Axelrod had announced that neurotransmitters do not merely stop working when they reach the post-synaptic nerve terminal. Rather, neurotransmitters are recaptured (reuptaken) by the pre-synaptic nerve ending, and used again for later transmissions. As Axelrod told the New York Times that year, "The decisive experiment took a couple of hours.... Working out all the details afterward took three years." Axelrod explained that epinephrine is held in tissues in an inactive form and is liberated by the nervous system when needed. From this research, Axelrod concluded that norepinephrine is the primary neurotransmitter of the sympathetic nervous system. Prior to Axelrod's discovery, scientists could only account for about three percent of epinephrine in the body, since at any given time the vast majority of epinephrine is in transit. By the early 1960s, using Axelrod's theory of neurotransmitter reuptake, scientists could trace about 98 percent of it, including that which is in transit. As Axelrod wrote in 1986, "[c]atecholamine transmitters in sympathetic nerves are in a state of flux, continually being synthesized, released, metabolized, and recaptured. In spite of these dynamic changes, the concentration of catecholamines in tissues remains at a constant level."
In 1962, Axelrod and postdoctoral researcher Richard J. Wurtman initiated a series of experiments that showed exactly how the tricyclics, a class of MAOI anti-depressants, stop the MAO enzyme from interfering with neurotransmitter reuptake. In 1963, they published their now-classic article, "A Sensitive and Specific Assay for the Estimation of Monoamine Oxidase." In 1964 Axelrod and postdoctoral assistant Solomon H. Snyder concluded that different types of antidepressants work in a variety of ways: some inhibit the MAO enzyme, some block neurotransmitters outright, and others perform some combination of inhibition and stimulation on neurotransmitter activity.
These discoveries about neurotransmitters have enabled neuroscientists to predict accurately why drugs, including antidepressants and the sympathomimetic amines, metabolize the way they do. Cocaine, for example, prevents post-synaptic nerve terminals from receiving norepinephrine; but the pre-synaptic nerve endings do not reuptake the excess neurotransmitters, either. Instead, the extra norepinephrine floating between synapses causes a chemical reaction that produces a temporary "high." Similarly, amphetamines release the neurotransmitter dopamine but block the post-synaptic terminal from receiving it, thus excessively stimulating the nervous system. These findings suggest that explanations for how medicinal or even recreational drugs work can be reduced to the effect (or lack thereof) that they have on norepinephrine and other neurotransmitters.