Interaction of serotonin autoreceptor antagonists in the rat dorsal raphe nucleus: an in vitro fast cyclic voltammetry study.
5-HT1A, 5-HT1B and 5-HT1D receptors are known to function as 5-HT autoreceptors in the rat dorsal raphe nucleus (DRN), modulating local 5-HT efflux. However, there are no studies on the simultaneous blockade of these receptors in the DRN. We investigated the effect of 5-HT1B and 5-HT1D receptor antagonists on 5-HT efflux in rat DRN, alone and in the presence of 5-HT1A receptor antagonists, using the technique of fast cyclic voltammetry. The 5-HT1A receptor antagonist, WAY 100635, and the 5-HT1B receptor antagonist, SB-224289, had no effect on 5-HT efflux while the 5-HT1B/1D receptor antagonist, GR 127935, produced a small decrease in 5-HT efflux. In contrast, the 5-HT1D receptor antagonist, BRL 15572, produced a significant increase in 5-HT efflux. Co-perfusion of WAY 100635 and SB-224289 significantly increased 5-HT efflux. In addition, WAY 100635 reversed the small inhibition of 5-HT efflux observed with GR 127935 but had no effect on the BRL 15572-induced increase. Antagonism of all three 5-HT autoreceptors with SB-224289, BRL 15572 and WAY 100635 significantly increased 5-HT efflux. These data confirm that 5-HT efflux within the DRN is under the control of 5-HT1A, 5-HT1B and 5-HT1D autoreceptors and elevation of 5-HT efflux was greatest following antagonism of 5-HT1A and 5-HT1B receptors.
Roberts
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Department of Neuroscience Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Essex, CM19 5AW, Harlow, UK. claire_roberts-1@sbphrd.com
Price
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GW
D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation; D004594:Electrophysiology; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*
D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists