5-HTib receptor postsynaptic

Administration of 5-HTib receptor agonists increases waking time and reduces REM sleep. This is consistent with recent evidence gathered from 5-HTiB-receptor knockout mice which exhibit more REM sleep and less SWS than the wild-type. Moreover, 5-HTib agonists reduce, while antagonists increase, REM sleep in the wild-type mouse, but neither type of compound has any effect in the knock-outs (Boutrel et al. 1999). Unfortunately, it is not known whether these actions are mediated by presynaptic, postsynaptic or heteroceptors and therefore whether 5-HT activity is increased or decreased. It is also not helped by the limited selectivity of test agents. 

Initially, it was proposed that the 5-HTjb receptor is located exclusively in the brain of the rat and some other rodents, whereas the 5-HTid receptor, a close species homolog, is specific to the guinea pig and higher mammalian species, including humans (Waeber et al., 1989). However, recent studies have characterized the 5-HTiB receptor also in the human brain (Bidmon et al., 2001 Varnas et al., 2005). The 5-HT, B receptor is linked to the inhibition of adenylate cyclase, and is located at presynaptic (5-HT axon terminals) and postsynaptic... 

Early studies identified 5-HTib receptors in rodent brain using radioligand binding techniques but failed to find them in human brain. The 5-HTib receptors are located both presynaptically, where they regulate the release of 5-HT (Fig. 14.4), and postsynaptically (31). Like 5-HTia receptors, they are negatively coupled to adenylate cyclase. (See 5-HT 1D Receptors for further related discussion.)... 

Thus it may be speculated that the 5-HTib/id receptors are supersensitive in depression, thereby leading to a reduced intersynaptic concentration of 5-HT with a consequent increase in the number of postsynaptic 5-HT2 receptor sites. However, only the development of highly selective 5-HTib/id antagonists will enable this hypothesis to be tested. 

The enhanced 5-HT release would probably act via the activation of postsynaptic 5-HT2 receptors that remain normosensitive after the 8-week SSRI treatment (el Mansari and Blier, 1997). Indeed, the response of orbitofrontal cortex neurons to 5-HT and 5-HT2 agonists is unaltered, whereas that to a 5-HTia agonist is decreased after such treatment. It has not been conclusively shown that these 5-HT2 receptors are located directly on the glutamatergic pyramidal neurons or on inhibitory GABA interneurons. Wherever their precise localization, the effect of 5-HT on these neurons, which send an excitatory output to the caudate nucleus, is inhibitory in nature, which could account for the dampening of the hyperactivity observed following successful SSRI treatment. These results clearly identify the terminal 5-HTib autoreceptor and the postsynaptic 5-HT2 receptors as potential novel targets for the treatment of OCD. 

HTlA receptors are expressed at both postsynaptic locations in 5-HT target areas (including the amygdala, hippocampus, and cortex) and presynaptic sites on 5-HT neurons in the raphe nuclei as somatodendritic autoreceptors. Because autoreceptors control neuronal firing and consequently 5-HT release, and because an increase in extracellular 5-HT levels during development (see previous section) has been implicated in anxiety, it initially was believed that the anxiety-like phenotype of 5-HTia receptor-deficient mice was because of increased 5-HT release. However, basal 5-HT levels are not altered, as measured by in vivo microdialysis, in 5-HTia receptor-deficient mice, presumably because of the compensatory action of presynaptic 5-HTib... 

Figure 1.10 Schematic model of a central serotonergic neurone indicating possible sites of drug action. Tryptophan is converted to 5-hydroxytryptophcm (5-HTP) by tryptophan hydroxylase (1) and this enzyme can be inhibited by parachlorophenylalanine (pCPA) but this compound has only experimental value. 5-HTP is then converted to 5-HT and stored in vesicles (2), a process disrupted by reserpine and tetrabenazine. 5-HT is released by a Ca -dependentprocess (3) parachloramfetamine andfenfluramine increase 5-HT release while activation of 5-HTib/d autoreceptors inhibits release (at the cell bodies this function is served by 5-HTia receptors). After release 5-HT activates a range of postsynaptic 5-HT receptors (4) to produce functional responses and...

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