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

transporter. The 5-HT transporter (SERT [SLC6A4]) is localized in
the membrane of serotonergic axon terminals (where it terminates
the action of 5-HT in the synapse) and in the membrane of platelets
(where it takes up 5-HT from the blood). This uptake system is the
means by which platelets acquire 5-HT, since they lack the enzymes
required for 5-HT synthesis. The 5-HT transporter and other
monoamine transporters have been cloned (Chapters 5, 8, and 12).
The amine transporters are distinct from VMAT2, which concentrates
amines in intracellular storage vesicles and is a nonspecific
amine carrier, whereas the 5-HT transporter is specific. The 5-HT
transporter is regulated by phosphorylation and subsequent internalization
(for a review, see Steiner et al., 2008), providing a mechanism
for dynamic regulation of serotonergic transmission.
The principal route of metabolism of 5-HT
involves oxidative deamination by monoamine oxidase
(MAO); the aldehyde intermediate thus formed is
converted to 5-hydroxyindole acetic acid (5-HIAA)
by aldehyde dehydrogenase (Figure 13–2). An alternative
route, reduction of the acetaldehyde to an alcohol,
5-hydroxytryptophol, is normally insignificant.
5-HIAA is actively transported out of the brain by a
process that is sensitive to the nonspecific transport
inhibitor, probenecid.
Since 5-HIAA formation accounts for nearly 100% of the
metabolism of 5-HT in brain, the turnover rate of brain 5-HT is
estimated by measuring the ratio of 5-HIAA/5-HT. 5-HIAA from
brain and peripheral sites of 5-HT storage and metabolism is excreted
in the urine along with small amounts of 5-hydroxytryptophol sulfate
or glucuronide conjugates. The usual range of urinary excretion
of 5-HIAA by a normal adult is 2-10 mg daily. Larger
amounts are excreted by patients with malignant carcinoid, providing
a reliable diagnostic test for the disease. Ingestion of ethanol
results in elevated amounts of NADH 2
(Chapter 23), which diverts
5-hydroxyindole acetaldehyde from the oxidative route to the
reductive pathway (Figure 13–2) and tends to increase the excretion
of 5-hydroxytryptophol and correspondingly reduce the excretion
of 5-HIAA.
Of the two isoforms of MAO (A and B) (see Chapter 8 and
Bortolato et al., 2008 for a review), MAO-A preferentially metabolizes
5-HT and norepinephrine; clorgyline is a specific inhibitor
of this enzyme. MAO-B prefers β-phenylethylamine and benzylamine
as substrates; low-dose selegiline is a relatively selective
inhibitor of MAO-B. Dopamine and tryptamine are metabolized
equally well by both isoforms. Neurons contain both isoforms of
MAO, localized primarily in the outer membrane of mitochondria.
MAO-B is the principal isoform in platelets, which contain large
amounts of 5-HT.
Other minor pathways of metabolism of 5-HT, such as sulfation
and O- or N-methylation, have been suggested. The latter
reaction could lead to formation of an endogenous psychotropic substance,
5-hydroxy-N,N-dimethyltryptamine (bufotenine; Figure 13–1).
However, other methylated indoleamines such as N,N-dimethyltryptamine
and 5-methoxy-N,N-dimethyltryptamine are far more
active hallucinogens and are more likely candidates to be endogenous
psychotomimetics.
PHYSIOLOGICAL FUNCTIONS
OF SEROTONIN
Multiple 5-HT Receptors
Based on data from studies of 5-HT’s actions in peripheral
tissues, researchers hypothesized that the multiple
actions of 5-HT involved interaction with distinct 5-HT
receptor subtypes. Extensive pharmacological characterization
and the cloning of receptor cDNAs have confirmed
this hypothesis (Barnes and Sharp, 1999;
Bockaert et al., 2006). The multiple 5-HT receptor subtypes
cloned comprise the largest known neurotransmitterreceptor
family. The 5-HT receptor subtypes are
expressed in distinct but often overlapping patterns
(Palacios et al., 1990) and are coupled to different transmembrane-signaling
mechanisms (Table 13–1). Most
5-HT receptors, especially the 5-HT 2C
receptor, can
activate G-proteins independently of agonists, a property
known as constitutive activity (Berg et al., 2008).
Four of seven currently recognized 5-HT receptor families
have defined functions (described later). The 5-HT 1
,
5-HT 2
, and 5-HT 4–7
receptor families are members of
the superfamily of GPCRs (Chapter 3). The 5-HT 3
receptor is a ligand-gated ion channel that gates Na +
and K + and has a predicted membrane topology akin to
that of the nicotinic cholinergic receptor (Chapter 11).
History of 5-HT Receptor Subtypes. In 1957, Gaddum and Picarelli
proposed the existence of two 5-HT receptor subtypes, M and D
receptors. M receptors were believed to be located on parasympathetic
nerve endings, controlling the release of acetylcholine,
whereas D receptors were thought to be located on smooth muscle.
Subsequent studies in both the periphery and brain were consistent
with the notion of multiple subtypes of 5-HT receptors (for a review,
see Sanders-Bush and Airey, 2008), now known to be members of
the superfamilies of GPCRs and ligand-gated ion channel receptors.
The current classification scheme (Hoyer et al., 1994) is based on
pharmacological properties, second-messenger function, and deduced
amino acid sequence, and includes seven subfamilies of 5-HT receptors
(Table 13–1).
The radioligand-binding studies of Peroutka and Snyder
(1979) provided the first definitive evidence for two distinct recognition
sites for 5-HT. 5-HT 1
receptors had a high affinity for [ 3 H]5-HT,
while 5-HT 2
receptors had a low affinity for [ 3 H]5-HT and a high
affinity for [ 3 H]spiperone. Subsequently, high affinity for 5-HT was
used as a primary criterion for classifying a receptor subtype as a
member of the 5-HT 1
receptor family. This classification strategy
proved to be invalid; for example, a receptor expressed in the choroid
plexus was named the 5-HT 1C
receptor because it was the third
receptor shown to have a high affinity for 5-HT. However, based on
its pharmacological properties, second-messenger function, and
deduced amino acid sequence, the 5-HT 1C
receptor clearly belonged
to the 5-HT 2
receptor family and was subsequently renamed the 5-HT 2C
receptor. Evidence suggests that the 5-HT 1Dβ
receptor is the human
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CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE