5-HT_1D Receptors Regulate 5-HT Release in the Rat Raphe Nuclei

Abstract

The aim of the present study was to characterize the pharmacological profile of 5-hydroxytryptamine (5-HT) receptors modulating 5-HT release in the mesencephalic raphe region. In a first series of experiments, differential normal pulse voltammetry and nafion-coated electrodes were used to measure extracellular 5-HT in the dorsal raphe of anesthesized rats. The intravenous administration of the selective 5-HT_1A agonist 8-OH-DPAT (30 μg/kg) and the 5-HT₁ agonist TFMPP (0.5 mg/kg) reduced the 5-hydroxyindole signal by 23% and 18%, respectively. Pretreatment with the 5-HT_1A antagonist (+)WAY100135 (0.5 mg/kg IV) 30 minutes before the injection of the agonists, blocked the effect of 8-OH-DPAT but not that of TFMPP. The effect of TFMPP was blocked by (±)mianserin, a drug with high affinity for the rat 5-HT_1D receptor, suggesting a role of this receptor subtype in the modulation of 5-HT release at the cell body level of 5-HT neurons. This was confirmed by in vitro superfusion experiments using mesencephalic raphe slices. The prototypical 5-HT₁ agonist 5-carboxy-amiditryptamine (5-CT) and the 5-HT_1B1D agonist sumatriptan (1-1,000 nM) induced a concentration-dependent inhibition of the electrically evoked release of [³H]5-HT from preloaded raphe slices. 8-OH-DPAT (100 nM) produced an inhibitory effect similar to that of sumatriptan (100 nM). The selective 5-HT_1B agonist CP 93129 (10-10,000 nM), had no effect in raphe slices, but it dose dependently inhibited [³H]5-HT release from hippocampal slices where autoreceptors are of the 5-HT_1B subtype. The inhibitory effect of 5-CT was blocked by the 5-HT₁₂ antagonist methiothepin (1 μM), the 5-HT_1A antagonist S-UH-301 (1 μM), and the 5-HT_1B1D antagonist GR 127935 (1 μM). That of 8-OH-DPAT was blocked by S-UH-301 (1 μM) but not by GR 127935 (1 μM), and that of sumatriptan was blocked by GR 127935 (1 μM) but not by S-UH-301 (1 μM). These results show that, together with 5-HT_1A autoreceptors, 5-HT_1D receptors negatively modulate the somatodendritic release of 5-HT.

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