HTIB

HTIB = hydroxy p-tosyloxyiodo benzene Bovonsombat, P. McNelis. E. Tetrahedron, 1993, 49, 1525... 

The apparent reliance of enzyme activation on phosphorylation and intracellular Ca + gives a clue as to how the rate of 5-HT synthesis might be coupled to its impulse-evoked release. Certainly, the impulse-induced increase in intracellular Ca +, and/or activation of the G protein-coupled receptors that govern synthesis of cAMP, could modify the activity of tryptophan hydroxylase. Indeed, this could explain why activation of either somal 5-HTia autoreceptors in the Raphe nuclei (which depress the firing rate of 5-HT neurons) or terminal 5-HTib autoreceptors (which depress 5-HT release) can reduce the production of cAMP and attenuate 5-HT synthesis. 

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). 

An interesting development in this area is the possibility that there could be an endogenous ligand, for these receptors 5-HT-moduline. This is a tetrapeptide that is released from neurons and is claimed to be the first allosteric modulator of a G protein-coupled receptor to be identified so far. Functionally, 5-HT-moduline behaves like a 5-HTib antagonist and so increases terminal release of 5-HT (Massot et al. 1998) and it is thought that this could be an important step in maintaining a sustained increase in release of 5-HT during stress. 

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. 

Interest in this receptor has been generated by the possibility that its activation accounts for the anti-migraine effects of the non-selective 5-HTib/id agonist, sumatriptan. The exact process(es) that account for this action are unresolved but... 

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)...

A related strategy would be to inactivate the 5-HTib/id autoreceptors which are found on serotonergic nerve terminals and so prevent feedback inhibition of 5-HT release in the terminal field. These drugs would not prevent the impact of indirect activation of 5-HTia receptors, and the reduced neuronal firing, by SSRIs (described above), but they would augment 5-HT release in the terminal field once the presynaptic 5-HTia receptors have desensitised. Selective 5-HTib/id antagonists have been developed only recently but will doubtless soon be tested in humans. 

Sumatriptan is an agonist at 5-HTib and 5-HTid receptors. It has three distinct pharmacological actions. 

Direct attenuation of the excitability of neurons in the trigeminal nuclei, as 5-HTib/ 5-HTid receptors on pain transmission neurons in the trigeminal nucleus caudalis and in the upper cervical cord, are activated. Stimulation of these receptors is caused by second-generation triptans that cross the blood-brain barrier such as zolmitriptan, naratriptan, rizatriptan and eletriptan. 

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. 

NOTE The 5-HTia, 5-HTib, and 5-HT,c receptors were labeled with H-OH-DPAT, H-5-HT, and H-... 

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... 

Serotonin shares with other neurotransmitters the ability to promote W and to suppress REMS. However, 5-HT participates in a variety of functions in addition to regulation of the behavioral state. Thus, as depicted in Tables 9.4-9.8, 5-HTia, 5-HTib, 5-HT2A/2C. 5-HT3, and 5-HT7 receptors are present in structures that... 

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. 

In conclusion, based on neurochemical, electrophysiological, and neurophar-macological approaches, it is presently accepted that 5-HT functions to promote W and to inhibit REMS. Available evidence indicates that 5-HTiA, 5-HTiB, 5-HT2a. 5-HT2b, 5-HT2c, 5-HT3, and 5-HT7 receptors are involved in these effects. 

Bruinvels, A. T., Landwehrmeyer, B., Gustafson, E. L. et al. (1994). Localization of the 5-HTib, 5-HTiDct, 5-HTie and 5-HTlf receptor messenger RNA in rodent and primate brain. Neuropharmacology 33, 367-86. 

Monaca, C., Boutrel, B., Hen, R., Hamon, M. Adrien, J. (2003). 5-HTia/b receptor-mediated effects of the selective serotonin reuptake inhibitor citalopram, on sleep studies in 5-HTia and 5-HTib knockout mice. Neuropharmacology 28, 850-6. 

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. 

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