CHARACTERIZATION OF THE SEROTONIN(1A) RECEPTOR ANTAGONIST ACTIVITY OFWAY-100135 AND SPIPERONE

The effects of the putative serotonin (5-HT)(1A) receptor antagonists WAY-100135 (WAY) and spiperone on the neuronal activity recorded from medullary and dorsal raphe 5-HT neurons and the inferior cardiac sympa thetic nerve were investigated in chloralose anesthetized cats. We als o determined the effectiveness of WAY and spiperone to antagonize the sympathoinhibitory effects of the 5-HT1A agonist 8-hydroxy-(2-di-n-pro pylamino)tetralin (8-OH DPAT). Intravenous administration of both WAY and spiperone produced a dose-related inhibition of the firing of medu llary 5-HT neurons. WAY also inhibited firing of serotonergic neurons in the dorsal raphe nucleus. WAY treatment had no significant effect o n inferior cardiac sympathetic nerve discharge (SND), whereas spiperon e treatment caused a small, but significant, increase in SND. WAY trea tment did not significantly affect 8-OH DPAT-induced inhibition of uni t firing. Spiperone, however, did display antagonist activity at the p resynaptic autoreceptor site. WAY and spiperone pretreatments resulted in significant rightward shifts in the 8-OH DPAT inhibition of SND do se-response curves and reversed the depressant effects of 8-OH DPAT. T hese results suggest that WAY and spiperone act as 5-HT1A antagonists postsynaptically, but WAY appears to have more potent agonist efficacy at the S-HT1A presynaptic autoreceptor site in the cat. However, beca use all drugs were administered intravenously, conclusions regarding d irect effects of WAY and spiperone on 5-HT1A receptors must be made ca utiously.