ELECTROPHYSIOLOGICAL EFFECTS OF ETHOXYPHENYL)-1-PIPERAZINYL)ETHYL)-N-(2-PYRIDINYL) CYCLOHEXANE CARBOXAMIDE (WAY-100635) ON DORSAL RAPHE SEROTONERGIC NEURONS AND CA1 HIPPOCAMPAL PYRAMIDAL CELLS IN-VITRO

The aim of the present study was to examine the effects of ethoxypheny l)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 1 00635) on 5-HT1A receptor-mediated responses in the dorsal raphe nucle us (DRN) and the CA1 hippocampal region. In DRN slices superfused with WAY 100635 (10 nM), the majority of putative 5-HT neurons increased t heir firing rate (13 +/- 2% of baseline rate). in addition, WAY 100635 completely prevented the decrease in firing rate produced by 5-HT (3- 15 mu M), 8-OH-DPAT (10 nM), 5-carbox-amidotryptamine (20 nM) and leso pitron (100 nM). The antagonism exerted by WAY 100635 (IC50 = 0.95 +/- 0.12 nM against 15 mu M 5-HT) was fully surmounted by increasing the concentration of 5-HT to 300 mu M. In hippocampal slices, WAY 100635 ( 0.5-10 nM) did not alter the resting membrane potential or the membran e input resistance of intracellularly recorded CA1 pyramidal cells. Ho wever, WAY 100635 completely prevented(IC50 = 0.9-1.7 nM) the hyperpol arization and the decrease in membrane input resistance produced by 5- HT (15-30 mu M) and by 5-carboxamidotryptamine (50-300 nM). In contras t, WAY 100635 affected neither the block of action potential frequency adaptation and slow afterhyperpolarization produced by 5-HT (15 mu M) nor the hyperpolarization and decrease in membrane input resistance e voked by bath application of the GABA(B) receptor agonist baclofen (10 mu M). The cumulative concentration-hyperpolarization curve for 5-car boxamidotryptamine (3 nM-10 mu M) was shifted to the right by WAY 1006 35 (apparent K-b = 0.23 +/- 0.07 nM), and the latter drug also reduced the maximal response to the agonist. These data show that WAY 100635 is a potent antagonist at 5-HT1A receptors, both in the DRN and in the CA1 region of the hippocampus. The antagonism is apparently competiti ve in the DRN and partly noncompetitive in the hippocampus. Kinetic ch aracteristics of the antagonist-receptor interactions might account fo r these regional differences.