Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing.

1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours.