Somatodendritic Autoreceptors (5-HT1A)

Presynaptic Autoreceptors (5-HT1D)

FIGURE 11-2 Two classes of 5-HT autoreceptors with differential localizations. Somatodendritic 5-HT1A 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 human forebrain has different pharmacological properties and has been classified as 5-HT1D; this receptor modulates the release of 5-HT. Postsynaptic 5-HT1 receptors are also indicated.

the pertussis toxin-sensitive G7Go family of G proteins. The 5-HT1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons (Figure 11-2). Another subtype, the 5-HT1D receptor, functions as an autoreceptor on axon terminals, inhibiting 5-HT release. 5-HT1D receptors, abundantly expressed in the substantia nigra and basal ganglia, may regulate the firing rate of dopamine (DA)-containing cells and the release of DA at axonal terminals.

5-HT2 RECEPTORS The three subtypes of 5-HT2 receptors couple to pertussis toxin-insensitive G proteins (e.g., Gq and G11) and thence to PLC to generate diacylglycerol (a cofactor in the activation of PKC) and inositol trisphosphate (which mobilizes intracellular stores of Ca2+). 5-HT2A receptors are broadly distributed in the CNS, primarily in serotonergic terminal areas. High densities of 5-HT2A receptors are found in prefrontal, parietal, and somatosensory cortex, claustrum, and in platelets. 5-HT2A receptors in the GI tract are thought to correspond to the D subtype of 5-HT receptor. 5-HT2B receptors originally were described in stomach fundus. The expression of 5-HT2B receptor messenger RNA (mRNA) is highly restricted in the CNS. 5-HT2C receptors have a very high density in the choroid plexus, an epithelial tissue that is the primary site of cerebrospinal fluid production. The 5-HT2C receptor has been implicated in feeding behavior and susceptibility to seizure.

5-HT3 RECEPTORS The 5-HT3 receptor is the only monoamine neurotransmitter receptor that is known to function as a ligand-operated ion channel. The 5-HT3 receptor corresponds to the originally described M receptor. Activation of 5-HT3 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-HT3 receptors is found in the solitary tract nucleus and the area postrema. 5-HT3 receptors in both the GI tract and the CNS participate in the emetic response, providing an anatomical basis for the antiemetic property of 5-HT3 receptor antagonists.

5-HT4 RECEPTORS 5-HT4 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-HT4 receptors are located on neurons of the myenteric plexus and on smooth muscle and secretory cells. The 5-HT4 receptor is thought to evoke secretion in the alimentary tract and to facilitate the peristaltic reflex. 5-HT4 receptors couple to Gs to activate adeny-lyl cyclase, leading to a rise in intracellular levels of cyclic AMP, possibly accounting for the utility of prokinetic benzamides in GI disorders (see Chapter 37).

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