5-HTib receptor receptors

Impulse-evoked release of 5-HT, like that of noradrenaline, is subject to fine control by a system of autoreceptors, in particular 5-HTia receptors on the cell bodies of neurons in the Raphe nuclei and 5-HTib/id receptors on their terminals. Because these are all G /o protein-coupled receptors, their activation reduces the synthesis of cAMP so that 5-HTia agonists (or 5-HT itself) decrease neuronal excitability and the firing of Raphe neurons whereas activation of 5-HTib/id receptors seems to disrupt the molecular cascade that links the receptor with transmitter release (see Chapter 4). 

Probably the most notable feature of this receptor is the confusion arising from its classification and nomenclature Soon after characterisation of the 5-HTid receptor, which was found in certain species (e.g. the human) it was determined that this was in fact a variant of the 5-HTib receptor which had already been found in other species (e.g. the rat). These receptors were therefore regarded as species variants and came to be described as the 5-HTib/id subtype. Since then, another 5-HTi receptor subtype has been identified and current nomenclature dictates that this is the (new) 5-HTid receptor. 

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

Direct vasoconstriction is mediated by the stimulation of vascular 5-HTib receptors. These receptors are also found systemically, so coronary arteries also undergo vasoconstriction. Sumatriptan constricts cerebral arteries, but if the vasculature is normal, this does not affect rCBF. 

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... 

Monaca et al. (2003) examined the effect of the SSRI citalopram on REMS in 5-HTia and 5-HTib knockout mice. Citalopram suppressed REMS in wild-type and 5-HTib mice but not in 5-HT,A I mutants. The 5-HTja receptor antagonist WAY 100635 prevented the citalopram-induced inhibition of REMS in wild-type and 5-HTib knockout mice. However, pretreatment with the 5-HTib receptor antagonist GR 127935 [2 -methyl-4 -(5-methyl-(l,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid ((4-methoxy-piperazine-l-yl)-phenyl)amide] was ineffective in this respect. It was concluded that the action of citalopram on REMS in the mouse depends exclusively on the activation of 5-HT,A receptors. Notwithstanding this, there is unequivocal evidence showing that administration of selective 5-HTib receptor agonists suppresses REMS in the rat. 

Few studies have been published on the effect of 5-HTiB receptor ligands on sleep variables. Systemic administration of the selective 5-HTiB receptor agonists CGS 12066B [7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo(l,2-... 

The quantitation of spontaneous sleep-waking cycles in 5-HTiB receptor knockout mice has shown that REMS is increased whereas SWS is reduced during the light phase (Boutrel et al., 1999). On the other hand, systemic administration of CP-94,253 to wild-type mice tends to suppress REM, whereas the 5-HTiB antagonist GR 127935 induces the opposite effect. Thus, the limited available evidence indicates that 5-HTib receptor activation facilitates the occurrence of W and negatively influences REMS. 

Monti, J. M., Monti, D., Jantos, H. Ponzoni, A. (1995b). Effects of selective activation of the 5-HTib receptor with CP-94,253 on sleep and wakefulness in the rat. Neuropharmacology 34, 1647-51. 

Varnas, K., Hurd, Y. L. Hall, H. (2005). Regional expression of 5-HTib receptor mRNA in the human brain. Synapse 56, 21-8. 

Parker, E.M., Geisel, D.A., Iben, L.G., and Shapiro, R.S. A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-HTib receptors. 

More recently, it has been speculated that the 5-HTib/id receptors may have a role to play in depression and in the mode of action of antidepressants. These receptors appear to be located presynaptically where they control the release of 5-HT in experimental studies the non-selective S-HT antagonist methiothepin has antidepressant properties. 

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. 

Sumatriptan and several other "triptans" are selective agonists for 5-HTiD and 5-HTiB receptors. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors. These drugs have proved to be very effective in the treatment of acute migraine headache. The mechanism of action is discussed in more detail below under Clinical Pharmacology of Ergot Alkaloids. 

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