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

340
SECTION II
NEUROPHARMACOLOGY
5-HT 1A
Receptor
5-HT
– –
Somatodendritic
Autoreceptors (5-HT 1A )
5-HT 1D/1B
Receptor
5-HT
Presynaptic
Autoreceptors (5-HT 1D/1B )
Figure 13–3. Two classes of 5-HT autoreceptors with differential
localizations. Somatodendritic 5-HT 1A
autoreceptors decrease
raphe cell firing when activated by 5-HT released from axon collaterals
of the same or adjacent neurons. The receptor subtype
of the presynaptic autoreceptor on axon terminals in the forebrain
has different pharmacological properties and has been classified
as 5-HT 1D
(in humans) or 5-HT 1B
(in rodents). This
receptor modulates the release of 5-HT. Postsynaptic 5-HT 1
receptors are also indicated.
5-HT 3
Receptors. The 5-HT 3
receptor is the only
monoamine neurotransmitter receptor known to function
as a ligand-operated ion channel. The 5-HT 3
receptor
corresponds to Gaddum and Picarelli’s M receptor.
Activation of 5-HT 3
receptors elicits a rapidly desensitizing
depolarization, mediated by the gating of cations.
These receptors are located on parasympathetic terminals
in the GI tract, including vagal and splanchnic
afferents. In the CNS, a high density of 5-HT 3
receptors
is found in the solitary tract nucleus and in the area
postrema. 5-HT 3
receptors in both the GI tract and the
CNS participate in the emetic response, providing a
basis for the anti-emetic property of 5-HT 3
receptor
antagonists. The 5-HT 3
receptor, a pentameric ligandgated
channel, belongs to the Cys-loop receptor superfamily,
which includes the nicotinic cholinergic
receptor and the GABA A
receptor. The original, cloned
5-HT 3
receptor subunit forms functional pentameric
complexes that gate cations when expressed in Xenopus
oocytes or in cultured cells (Maricq et al., 1991). Five
genes (HTR3A-E) for 5-HT 3
receptor subunits have
now been cloned. Heteropentamers of the multiple gene
products exhibit distinct properties and anatomical distributions
(see Barnes et al., 2009).
5-HT 4
Receptors. 5-HT 4
receptors couple to G s
to activate
adenylyl cyclase, leading to an increase in intracellular
cyclic AMP. 5-HT 4
receptors are widely
distributed throughout the body. In the CNS, the receptors
are found on neurons of the superior and inferior
colliculi and in the hippocampus. In the GI tract, 5-HT 4
receptors are located on neurons of the myenteric
plexus and on smooth muscle and secretory cells. In the
GI tract, stimulation of the 5-HT 4
receptor is thought
to evoke secretion and to facilitate the peristaltic reflex.
The latter effect may explain the utility of prokinetic
benzamides in GI disorders (Chapter 46). Effects of
pharmacological manipulation of 5-HT 4
receptors on
memory and feeding in animal models suggest possible
clinical applications in the future (Bockaert et al. 2008).
Additional Cloned 5-HT Receptors. Two other cloned receptors, 5-
HT 6
and 5-HT 7
, are linked to activation of adenylyl cyclase. Multiple
splice variants of the 5-HT 7
receptor have been found, although functional
distinctions are not clear. The absence of selective agonists
and antagonists has foiled definitive studies of the role of the 5-HT 6
and 5-HT 7
receptors. Circumstantial evidence suggests that 5-HT 7
receptors play a role in the relaxation of smooth muscle in the GI
tract and the vasculature. The atypical antipsychotic drug clozapine
has a high affinity for 5-HT 6
and 5-HT 7
receptors; whether this property
is related to the broader effectiveness of clozapine compared to
conventional antipsychotic drugs is not known (Chapter 16). Two
subtypes of the 5-HT 5
receptor have been cloned; although the 5-
HT 5A
receptor has been shown to inhibit adenylyl cyclase, functional
coupling of the cloned 5-HT 5B
receptor has not yet been described.
Actions of 5-HT in Physiological Systems
Platelets. Platelets differ from other formed elements of blood in
expressing mechanisms for uptake, storage, and endocytotic release
of 5-HT. 5-HT is not synthesized in platelets, but is taken up from
the circulation and stored in secretory granules by active transport,
similar to the uptake and storage of serotonin by serotonergic nerve
terminals. Thus, Na + -dependent transport across the surface membrane
of platelets, via the 5-HT transporter, is followed by VMAT2-
mediated uptake into dense core granules creating a gradient of
5-HT as high as 1000:1 with an internal concentration of 0.6 M in
the dense core storage vesicles. Measuring the rate of Na + -dependent
5-HT uptake by platelets provides a sensitive assay for 5-HT uptake
inhibitors.
Main functions of platelets include adhesion, aggregation,
and thrombus formation to plug holes in the endothelium; conversely,
the functional integrity of the endothelium is critical for
platelet action. A complex local interplay of multiple factors, including
5-HT, regulates thrombosis and hemostasis (Chapters 30 and 33).
When platelets make contact with injured endothelium, they release
substances that promote platelet aggregation, and secondarily, they
release 5-HT (Figure 13–4). 5-HT binds to platelet 5-HT 2A
receptors
and elicits a weak aggregation response that is markedly augmented
by the presence of collagen. If the damaged blood vessel is
injured to a depth where vascular smooth muscle is exposed, 5-HT
exerts a direct vasoconstrictor effect, thereby contributing to hemostasis,
which is enhanced by locally released autocoids (thromboxane
A 2
, kinins, and vasoactive peptides). Conversely, 5-HT may
interact with endothelial cells to stimulate production of NO and
antagonize its own vasoconstrictor action, as well as the vasoconstriction
produced by other locally released agents.
Cardiovascular System. The classical response of blood vessels to
5-HT is contraction, particularly in the splanchnic, renal, pulmonary,