5-HT1A and 5-HT2 receptors differentially regulate the excitability of 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro

We have used intracellular recording techniques to examine the effects of 5 -hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the gui nea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30-300 muM) had t wo opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previou sly in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neur ones, which appeared to involve the activation of an inwardly rectifying K conductance. This hyperpolarizing response was blocked by the 5-HT1A recep tor-selective antagonist WAY-100635 (30-100 nM). In the presence of WAY-100 635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparen t input resistance of the neurone, likely due to the suppression of a K+ co nductance. Like the hyperpolarizing response to 5-HT, this depolarization c ould be recorded in the presence of the Na+ channel blocker tetrodotoxin. I n addition, the response was not significantly attenuated by the alpha (1)- adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of alpha (1)-adr enoceptors by 5-HT. The 5-HT3 receptor antagonist granisetron (1 muM) and t he 5-HT4 receptor antagonist SB 204070 (100 nM) failed to reduce the depola rizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 muM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT 2 receptors. (C) 2001 Elsevier Science B.V. All rights reserved.