5-HTiA receptor

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). 

Beckett, S and Marsden, CA (1997) The effect of central and systemic injection of the 5-HTia receptor agonist 8-OHDPAT and the 5-HTia receptor antagonist WAY100635 on peri-aquaductal grey-induced defence behaviour. J. Psychopharmacol. 11 35 0. 

Cao, BJ and Rodgers, RJ (1997) Influence of 5-HTia receptor antagonism on plus-maze behaviour in mice. II WAY 100635, SDZ 216-525 and NAN-190. Pharmacol. Biochem. Behav. 58 593-603. 

Przegalinski, E, Chojnacka-Wojcik, E and Filip, M (1992) Stimulation of postsynaptic 5-HTia receptors is responsible for the anticonflict effect of ipsapirone in rats. J. Pharm. Pharmac. 44 780-782. 

There is a good deal of evidence that the therapeutic effects of antidepressants could involve adaptive changes in 5-HTia receptors. Postsynaptic 5-HTia receptor responses became implicated because the hyperpolarisation of hippocampal CA3 pyramidal neurons that follows ionophoretic administration of 5-HT was found to be increased after chronic treatment with most (but not all) antidepressants (Chaput, de Montigny and Blier 1991). Others suggested that antidepressants attenuate postsynaptic 5-HTja responses because the hypothermia, evoked by their activation, is diminished by antidepressants (Martin et al. 1992). 

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

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. 

Arylpiperazines have immensely important effects on various and diverse biological targets, in particular on CNS receptors. In the case of serotonin (5-HT) receptors, compounds containing this arylpiperazine moiety represent the largest systematically studied class of 5-HTia receptor ligands [63]. Structural alterations within long-chain arylpiperazines (LCAPs) occur mainly at the two opposite ends of a molecule and have been described by many authors [64-71]. 

Table 4 SAR data with molecular structures of 5-HTia receptor ligands reported by Palu-chowska et al. (2002) [63]...

Scheme 2 The steps involved in the synthesis of the 5-HTia receptor ligands reported hy Paluchowska et al. (2002) [63], 1 PhsP, NBS, EtsN, CH2CI2, 0-25 °C 11 BOP, EtsN, CH3CN, rt 111 20% K2CO3 - CHCI3, rt IV xylene, reflux V pyridine, reflux... 

While all the achievable conformations of the constrained compounds belong to an extended family—as indicated by molecular modehng studies— the hypothesis that such conformations are responsible for the blockade of postsynaptic 5-HTia receptors has been confirmed by Paluchowska et al. [63]. 

The 5-HTia receptor is located on the soma and the dendrites (somatodendritic autoreceptor) of 5-HT neurons, and at postsynaptic sites. Wang Aghajanian (1977), and Aghajanian Lakoski (1984) have shown that the somatodendritic autoreceptor mediates collateral inhibition, and that the ionic basis... 

Currently, a number of ligands are available that show affinity for the 5-HTiA-receptor binding site in rat and cat brain. They include 8-OH-DPAT... 

Systemic injection of flesinoxan increases W and reduces SWS and REMS in the rat (Monti Jantos, 2003). Similar effects have been observed following the administration of 8-OH-DPAT to vehicle-treated and serotonin-depleted animals (Dugovic Wauquier, 1987 Monti Jantos, 1992 Monti et al, 1990, 1994). Pretreatment with (—)pindolol or p-MPPI reverses the effect of 8-OH-DPAT on W and SWS (Monti Jantos, 1992 Sorensen et al, 2001). All these findings indicate that the postsynaptic 5-HTia receptor has a role in the occurrence of arousal. 

Austin, M. C Weikel, J. A., Arango, V. 8r Mann, J. J. (1994). Localization of serotonin 5-HTia receptor mRNA in neurons of the human brainstem. Synapse 18,... 

Boutrel, B Monaca, C., Hen, R., Hamon, M. Adrien, J. (2002). Involvement of 5-HTia receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep studies in 5-HT1A knock-out mice. J. Neurosci. 22, 4686-92. 

Fletcher, A., Forster, E. A., Bill, D. J. et al. (1996). Electrophysiological, biochemical, neurohormonal and behavioral studies with WAY-100635, a potent, selective and silent 5-HTia receptor antagonist. Behav. Brain Res. 73, 337-53. 

Monti, J. M. Jantos, H. (1992). Dose-dependent effects of the 5-HTia receptor agonist 8-OHDPAT on sleep and wakefulness in the rat. J. Sleep Res. 1, 169-75. 

Monti, J. M., Jantos, H. Monti, D. (2000). Dorsal raphe nucleus administration of 5-HTia receptor agonist and antagonists effect on rapid eye movement sleep in the rat. Sleep Res. Online 3, 29-34. 

Sorensen, E., Gronli, J., Bjorvatn, B., Bjorkum, A. Ursin, R. (2001). Sleep and waking following microdialysis perfusion of the selective 5-HTia receptor antagonist p-MPPI into the dorsal raphe nucleus in the freely moving rat. Brain Res. 897, 122 30. 

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