Functional characterization of 5‐HT_1D autoreceptors on the modulation of 5‐HT release in guinea‐pig mesencephalic raphe, hippocampus and frontal cortex

Abstract

1 The aims of the present study were (i) to characterize further the pharmacology of 5-HTID autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HTID receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HTlD autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase.2 In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HTID/IB receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HTIB 3 The inhibitory effect of sumatriptan on K+-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HTID receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4 The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HTID autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HTlD autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5-HTlD autoreceptor activated by sumatriptan, another subtype of 5-HT autoreceptor is activated by 5-MeOT in the hippocampus. 5 Following a 3-week treatment with the selective 5-HT reuptake inhibitor, paroxetine (10 mg kg-' day-') and a 48 h washout period, the electrically evoked release of [3H]-5-HT was enhanced in mesencephalic raphe, hippocampus and frontal cortex slices. There was an attenuation of the capacity of sumatriptan to inhibit the evoked release of [3H]-5-HT from mesencephalic raphe slices but not from frontal cortex and hippocampus slices. Only in the latter structure was the suppressant effect of 5-MeOT attenuated. After a 3-week treatment with the reversible type-A monoamine oxidase inhibitor, befloxatone (0.75 mg kg-' day-') and 48 h washout period, the effectiveness of sumatriptan and 5-MeOT on the evoked release of [3H]-5-HT was unaltered in the same brain structures.6 The enhancement of [3H]-5-HT release by long-term paroxetine treatment is possibly due to a desensitization of 5-HTID autoreceptors activated by sumatriptan in mesencephalic raphe and by terminal 5-HT autoreceptors activated by 5-MeOT in hippocampus. In the case of the frontal cortex, it appears that 5-MeOT and sumatriptan may act on the same 5-HTlD autoreceptor which is not desensitized either after paroxetine or befloxatone treatment, as previously reported.

Specific interaction of 5-HT-moduline with human 5-HT1b as well as 5-HT1d receptors expressed in transfected cultured cells

“…The role of the 5-HT 1D receptor as autoand heteroreceptor is less clear although the group of Blier (Pineyro et al 1995;El Mansari and Blier 1996) demonstrated the inhibitory function of these receptors on the evoked release of 5-HT in the raphe area. The results presented by these authors are in favor of a somatodendritic localization of these receptors.…”

The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat

“…The raphe-hippocampal pathway is one of the numerous ascending serotonergic projections in the brain [55]. The caudate nucleus also represents an important projection field for serotonergic neurons located in the raphe nuclei [162,168].…”

“…It has been shown that sustained administration of paroxetine induces desensitization 5-HT 1A autoreceptors and also decreases effectiveness of 5-HT 1D receptor activation in reducing 5-HT release from rat raphe nuclei slices [125]. Desensitization of 5-HT 1D receptors in mesencephalic raphe and in hippocampus of the guinea pig may also occur after longterm paroxetine administration [55]. Repeated administration of 5-HT reuptake blockers leads to desensitization of terminal 5-HT B/1D autoreceptors in different 5-HT projection areas and this was indicated by a reduced efficacy of 5-HT 1B/1D agonists to inhibit 5-HT release [126].…”

“…Raphe nuclei possess at least two autoreceptor mechanisms that control 5-HT release: one directly mediated by 5-HT 1B and/or 5-HT 1D receptors and the other one indirectly mediated by 5-HT 1A autoreceptors that also modulate neural firing rate [15]. The release inhibitory 5-HT 1B receptors are situated on recurrent axon collaterals and axon terminals within the raphe nuclei [4,49,55,56], these receptors exert small effect on the firing of these neurons [136]. Apart, 5-HT 1B autoreceptors, inhibition of 5-HT 1D receptor-mediated 5-HT releases in the raphe nuclei is also independent from regulation of neuronal firing [47].…”

Effect of Ergotamine on Serotonin-Mediated Responses in the Rodent and Human Brain

“…This inhibition suggested that ergotamine could act as a 5-HT 1B and a 5-HT 1D receptor agonist at terminal autoreceptors in the rat and guinea pig brain, respectively. However, the selective and potent 5-HT 1B/1D receptor antagonist GR 127935, which in similar experiments blocks the inhibitory effect of 5-HT 1B and 5-HT 1D receptor agonists (Piñeyro et al 1995;El Mansari and Blier 1996), did not prevent the inhibitory effect of ergotamine on evoked [ HT, and this effect is antagonized by nonselective 5-HT receptor antagonists, such as methiothepin or metergoline a well as the 5-HT 1A/1B receptor antagonist cyanopindolol (Feuerstein et al 1987;Maura et al 1987), and other antagonists that possess high affinity for 5-HT 1B binding sites. The receptor mediating the inhibitory effect of ergotamine on evoked [ (Piñeyro et al 1995).…”