DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

5-Hydroxytryptamine
(Serotonin) and Dopamine
Elaine Sanders-Bush and
Lisa Hazelwood
5-Hydroxytryptamine (5-HT, serotonin) and dopamine
(DA) are neurotransmitters in the central nervous system
(CNS) and also have prominent peripheral actions.
5-HT is found in high concentrations in enterochromaffin
cells throughout the GI tract, in storage granules in
platelets, and broadly throughout the CNS. 5-HT regulates
smooth muscle in the cardiovascular system and
the GI tract and enhances platelet aggregation. The
highest concentrations of DA are found in the brain;
dopamine stores are also present peripherally in the
adrenal medulla and the transmitter is detectable in the
plexuses of the GI tract and in enteric nervous system.
DA modulates peripheral vascular tone to modulate
renal perfusion, heart rate, and vasoconstriction/dilation.
Fourteen 5-HT receptor subtypes and five DA-receptor
subtypes have been delineated by pharmacological
analyses and cDNA cloning. The availability of cloned
receptors has allowed the development of subtypeselective
drugs and the elucidation of actions of these
neurotransmitters at a molecular level. Increasingly,
therapeutic goals are being achieved by drugs that target
selectively one or more of the subtypes of 5-HT
or DA receptors, or that act on a combination of both
5-HT and DA receptors.
5-HT and DA are widely distributed in the animal
and plant kingdoms. Several important laboratory
invertebrate models have serotonergic and dopaminergic
systems, including the fruit fly and nematode. 5-HT
and DA are considered below in separate sections.
5-HYDROXYTRYPTAMINE
History. In the 1930s, Erspamer began to study the distribution of
enterochromaffin cells, which stained with a reagent for indoles.
The highest concentrations were found in GI mucosa, followed
by platelets and the CNS. Soon thereafter, Page and colleagues
isolated and chemically characterized a vasoconstrictor substance
released from platelets in clotting blood. This substance, named
serotonin, was shown to be identical to the indole isolated by
Erspamer. Subsequent discovery of biosynthetic and degradative
pathways for 5-HT and clinical presentation of patients with carcinoid
tumors of intestinal enterochromaffin cells spurred interest
in 5-HT. The gross effects of 5-HT, produced in excess in malignant
carcinoid, gave some indication of the physiologic and pharmacologic
actions of 5-HT, as did the identification of several
naturally occurring and semi-synthetic tryptamine-like substances
that were hallucinogenic and induced behavioral effects similar to
those observed in carcinoid patients. In the mid-1950s, the discovery
that the pronounced behavioral effects of reserpine are accompanied
by a profound decrease in brain 5-HT led to the proposal
that serotonin may function as a neurotransmitter in the mammalian
CNS.
Sources and Chemistry. 5-HT [3-(β-aminoethyl)-5-hydroxyindole]
is present in vertebrates, tunicates, mollusks, arthropods, coelenterates,
fruits, and nuts. It is also a component of venoms, including
those of the common stinging nettle and of wasps and scorpions.
Numerous synthetic or naturally occurring congeners of 5-HT have
pharmacological activity (see Figure 13–1 for chemical structures).
Many of the N- and O-methylated indoleamines, such as N,Ndimethyltryptamine,
are hallucinogens. Because these compounds
are behaviorally active and might be synthesized by known metabolic
pathways, they have long been considered candidates for
endogenous psychotomimetic substances, potentially responsible for
some psychotic behaviors. Another close relative of 5-HT, melatonin
(5-methoxy-N-acetyltryptamine), is formed by sequential N-acetylation
and O-methylation (Figure 13–2). Melatonin, not to be confused
with melanin, is the principal indoleamine in the pineal gland, where
it may be said to constitute a pigment of the imagination. Its synthesis
is controlled by external factors including environmental light.
Melatonin induces pigment lightening in skin cells and suppresses
ovarian functions; it also serves a role in regulating biological
rhythms and shows promise in the treatment of jet lag and other sleep
disturbances (Cajochen et al., 2003).
Synthesis and Metabolism of 5-HT. 5-HT is synthesized
by a two-step pathway from the essential amino