5-HT autoreceptors in the regulation of 5-HT release from guinea pig raphe nucleus and hypothalamus

5-HT autoreceptors involved in the regulation of 5-HT release in the guinea pig dorsal raphe nucleus have been studied in comparison with those in the hypothalamus. In vitro release was measured in slices of raphe and hypothalamus prelabelled with [³H]5-HT, superfused with Krebs solution and depolarized electrically. The non-selective 5-HT receptor agonist, 5-carboxamidotryptamine (5-CT) (0.1–10 nM for raphe; 1–100 nM for hypothalamus) and antagonist, methiothepin (10–1000 nM), decreased and increased, respectively, the release of [³H]5-HT evoked by electrical stimulation in either of these regions when given alone. The selective 5-HT_1B/D receptor antagonist, GR127935 (100–1000 nM), and the 5-HT_1D receptor antagonist, ketanserin (300–1000 nM), had no significant effect on this release in either of these regions. Methiothepin and GR127935 (100–1000 nM) shifted to the right the concentration-effect curve of 5-CT in both the raphe and the hypothalamus. At 300 nM, ketanserin shifted to the right the concentration-effect curve of 5-CT in the raphe but did not modify the 5-CT curve in the hypothalamus. In microdialysis experiments ketanserin, applied locally at 10 μM, increased the extracellular levels of 5-HT in the dorsal raphe nucleus of the freely moving guinea pig, whereas 5-HT levels were unchanged in the hypothalamus. Ketanserin at 1 μM did not affect the decrease in 5-HT output induced by the selective 5-HT_1B/D receptor agonist, naratriptan (used at 10 μM in raphe and 0.1 μM in hypothalamus), in the raphe or the hypothalamus. In the raphe, WAY100635, a 5-HT_1A receptor antagonist, at 1 μM, did not prevent naratriptan (10 μM) from reducing the extracellular levels of 5-HT. These results suggest that, in the conditions used in this study, the release of 5-HT in the dorsal raphe nucleus is possibly modulated in part by 5-HT_1B receptors but essentially the control is through 5-HT receptors whose subtype is still to be determined. In the hypothalamus, however, it is clear that only 5-HT_1B receptors are involved in the modulation of 5-HT neurotransmission.