CHAPTER 7Neurotransmitters & Neuromodulators 137receptors (from 5-HT 1 through 5-HT 7 receptors). Within the
5-HT 1 group are the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and
5-HT1F subtypes. Within the 5-HT 2 group there are 5-HT2A,
5-HT2B, and 5-HT2C subtypes. There are two 5-HT 5 sub-
types: 5-HT5A and 5-HT5B. Most of these are G protein-cou-
pled receptors and affect adenylyl cyclase or phospholipase C
(Table 7–2). However, the 5-HT 3 receptors, like nicotinic
cholinergic receptors, are ligand-gated ion channels. Some of
the serotonin receptors are presynaptic, and others are
postsynaptic.
5-HT2A receptors mediate platelet aggregation and smooth
muscle contraction. Mice in which the gene for 5-HT2C
receptors has been knocked out are obese as a result of
increased food intake despite normal responses to leptin, and
they are prone to fatal seizures. 5-HT 3 receptors are present
in the gastrointestinal tract and the area postrema and are
related to vomiting. 5-HT 4 receptors are also present in the
gastrointestinal tract, where they facilitate secretion and
peristalsis, and in the brain. 5-HT 6 and 5-HT 7 receptors in
the brain are distributed throughout the limbic system, and
the 5-HT 6 receptors have a high affinity for antidepressant
drugs.
Histamine
Histaminergic neurons have their cell bodies in the tubero-
mammillary nucleus of the posterior hypothalamus, and
their axons project to all parts of the brain, including the ce-
rebral cortex and the spinal cord. Histamine is also found in
cells in the gastric mucosa and in heparin-containing cells
called mast cells that are plentiful in the anterior and poster-
ior lobes of the pituitary gland as well as at body surfaces.
Histamine is formed by decarboxylation of the amino acid
histidine (Figure 7–1). Histamine is converted to methylhista-
mine or, alternatively, to imidazoleacetic acid. The latter reac-
tion is quantitatively less important in humans. It requires the
enzyme diamine oxidase (histaminase) rather than MAO,
even though MAO catalyzes the oxidation of methylhistamine
to methylimidazoleacetic acid.
The three known types of histamine receptors—H 1 , H 2 ,
and H 3 —are all found in both peripheral tissues and the
brain. Most, if not all, of the H 3 receptors are presynaptic, and
they mediate inhibition of the release of histamine and other
transmitters via a G protein. H 1 receptors activate phospholi-
pase C, and H 2 receptors increase the intracellular cAMP con-
centration. The function of this diffuse histaminergic system
is unknown, but evidence links brain histamine to arousal,FIGURE 7–6 Biochemical events at serotonergic synapses. 5-
HTP, 5-hydroxytryptophan; 5-HT, 5-hydroxytryptamine (serotonin); 5-
HIAA, 5-hydroxyindoleacetic acid; X, serotonin receptor. For clarity, the
presynaptic receptors have been omitted.
Serotonergic
neuronPostsynaptic
tissueMAO5-HT5-HT5-HTP5-HIAAL-TryptophanReuptakeCLINICAL BOX 7–2
Role of Serotonin in Mood & Behavior
The hallucinogenic agent lysergic acid diethylamide (LSD)
is a serotonin agonist that produces its effects by activating
5-HT 2 receptors in the brain. The transient hallucinations and
other mental aberrations produced by this drug were discov-
ered when the chemist who synthesized it inhaled some by
accident. Its discovery called attention to the correlation
between behavior and variations in brain serotonin con-
tent. Psilocin (and its phosphorylated form, psilocybin), a
substance found in certain mushrooms, and N,N-dimethyl-
tryptamine (DMT) are also hallucinogenic and, like seroto-
nin, are derivatives of tryptamine. 2,5-Dimethoxy-4-methyl-
amphetamine (DOM) and mescaline and its congeners, the
other true hallucinogens, are phenylethylamines rather than
indolamines. However, all these hallucinogens appear to
exert their effects by binding to 5-HT 2 receptors. 3,4-Meth-
ylenedioxymethamphetamine, a drug known as MDMA or
ecstasy, is a popular drug of abuse. It produces euphoria,
but this is followed by difficulty in concentrating, depression,
and, in monkeys, insomnia. The drug causes release of sero-
tonin followed by serotonin depletion; the euphoria may be
due to the release and the later symptoms to the depletion.
Drugs that increase extracellular norepinephrine levels in
the brain elevate mood, and drugs that decrease extracellu-
lar norepinephrine levels cause depression. However, indi-
viduals with congenital dopamine β-hydroxylase (DBH) defi-
ciency are normal as far as mood is concerned. Drugs that
inhibit norepinephrine reuptake were of considerable value
in the treatment of depression, but these drugs also inhibit
serotonin reuptake. It is also known that the primary seroto-
nin metabolite 5-HIAA is low in CSF of depressed individu-
als. Drugs such as fluoxetine (Prozac), which inhibit seroto-
nin reuptake without affecting norepinephrine reuptake, are
effective as antidepressants. Thus, the focus in treating clini-
cal depression has shifted from norepinephrine to serotonin.