Thomas F. Murray
Creighton University, Omaha, NE, USA
Psychopharmacology had its beginnings in the early 1950s and has steadily grown into one of the major areas of pharmacology and psychiatry. Before the advent of these psychoactive drugs, various central nervous system (CNS) agents, such as the narcotics, barbiturates, and stimulants were known, but none of these represented important psychotherapeutic agents, and psychiatrists had an extremely limited chemotherapeutic armamentarium. The initial breakthrough came when the drugs, chlorpromazine and reserpine, proved to be effective antipsychotic and anti‐schizophrenic agents.
Soon after the development of the antipsychotic (or neuroleptic) drugs, the antidepressant action of iproniazid was discovered, and this therapeutic effect became correlated with the inhibition of monoamine oxidase (MAO) and a consequent rise in brain biogenic amines (serotonin, dopamine, and norepinephrine). A great deal of research has been carried out on a diverse array of psychoactive drugs in attempts to more fully understand their mechanism of action. From all of this research one striking common denominator emerges, namely, that many of these agents appear to modify in some way biogenic amines found in the CNS. Almost all of the psychoactive drugs, ranging from LSD and other hallucinogens to the antipsychotics and antidepressants, as well as other centrally acting agents, such as medetomidine, clomipramine, and l‐deprenyl, are now associated with biogenic amine mechanisms.
The Biogenic Amines
The term “biogenic amines,” as used in psychopharmacology, includes the two catecholamines dopamine (DA) and norepinephrine (NE), and the indoleamine, 5‐hydroxytryptamine (5‐HT, serotonin), the structures of which are indicated in Figure 3.1. Norepinephrine has been known for many years as the transmitter in peripheral sympathetic neurons, and much is now known regarding its biosynthesis, storage, uptake, release, and degradation mechanisms. Serotonin has also been extensively investigated; and while its distribution is less ubiquitous, it also regulates critical functions in the CNS. Dopamine, which until the early 1960s, was considered primarily as a precursor of NE, is now established as a CNS transmitter in its own right. Its presence in the neostriatum and limbic system in high concentrations initially led to speculation of its possible role in CNS function. These observations and other related studies have demonstrated that degeneration of DA neurons of the nigro‐striatal track is involved in Parkinson’s disease. In fact, the use of its precursor, 1‐dopa, in the treatment of this disease was historically based on this concept. The development of histochemical fluorescence techniques for the visualization of the biogenic amines within the nerve cell bodies and terminals has permitted the mapping of the biogenic amine pathways throughout the various parts of the CNS. From such investigations it is now known that NE and 5‐HT neurons, whose cell bodies are found largely in the locus coeruleus and midbrain raphe nuclei, respectively, terminate more or less in the same regions of the CNS. DA cell bodies originate largely in the substantia nigra, the ventral tegmental area, and in the arcuate nucleus of the hypothalamus, and their neurons terminate in the neostriatum; limbic structures; and the median eminence and pituitary, respectively.
Serotonin was first chemically identified in the 1940s, although its existence in the gastrointestinal tract was previously known. Its presence in blood serum and platelets, and the fact that it exerted vasoconstrictor activity led to the derivation of the name “serotonin.” It was, however, only its discovery in mammalian brain that initiated the extensive neurochemical and pharmacologic investigations which have led to our current understanding of serotonin as a central neurotransmitter.
Early interest in serotonin functions in the brain intensified with the recognition that many hallucinogenic drugs (e.g. LSD) were structurally related to the serotonin molecule. Because these hallucinogens act like serotonin, it was postulated that the hallucinogenic activity of LSD is related to its serotonergic agonist activity. Thus, the compound bufotenin, or N,N‐dimethylserotonin, a very close analog of serotonin, is a potent hallucinogen when administered centrally. Several other compounds, such as the substances psilocybin and psilocin, the indoleamines found in the “magic” mushrooms of Mexico, and other drugs of abuse, such as the dimethyl‐ and diethyl‐analogs of tryptamine, have the basic indole ethylamine structure. Hallucinogens are now known to mediate many of their psychoactive effects by activating serotonin 2A receptors (5‐HT2AR). The 5‐HT2AR is highly expressed on pyramidal neurons in the frontal cortex and has been implicated in several mental and behavioral disorders, including schizophrenia, anxiety, and depression (Schmid and Bohn 2010).
Inasmuch as serotonin is found in many cells outside of the central nervous system that are not neurons, only about 1–2% of the whole body serotonin content is found in the brain. Serotonergic neurons synthesize this transmitter, beginning with the conversion of dietary tryptophan to 5‐hydroxytryptophan. Plasma tryptophan varies as a function of diet and elimination of dietary tryptophan can dramatically lower levels of serotonin in the brain. Following the production of 5‐hydroxytryptophan by hydroxylation of tryptophan in serotonergic neurons, the 5‐hydroxytryptophan is rapidly decarboxylated to produce serotonin (5‐hydroxytryptamine). The serotonin precursor, 5‐hydroxytryptophan is sold as an over‐the‐counter dietary supplement (sometimes termed Griffonia seed extract) for its claimed ability to treat conditions such as depression, headaches, obesity, and insomnia in humans (and animals). The oral administration of 5‐hydroxytryptophan results in rapid absorption from the gastrointestinal tract and in turn readily crosses the blood–brain barrier (Gwaltney‐Brant et al. 2000). This 5‐hydroxytryptophan can be rapidly converted to serotonin in the brain and the spinal cord. Excessive stimulation of serotonin receptors due to dramatic elevations of 5‐HT causes a “serotonin syndrome” that may be associated with muscle rigidity, myoclonus, salivation, agitation, and hyperthermia in animals and humans. The most common cause of this syndrome is an interaction between a monoamine oxidase inhibitor and a selective serotonin reuptake inhibitor. The accidental ingestion of 5‐hydroxytryptophan by dogs, however, has been documented to result in a life‐threatening syndrome resembling a serotonin syndrome (Gwaltney‐Brant et al. 2000). A review of 21 cases of accidental 5‐hydroxytryptophan by dogs indicated that ingestion of a single 500 mg capsule of these dietary supplements would be sufficient to produce adverse sequelae in dogs.
In the mammalian brain, serotonergic neurons are localized to clusters of cell bodies of the pons and brain stem termed the raphe nuclei (Figure 3.2