S-16924 [(R)-2-{1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic withmarked serotonin(1A) agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol

S-16924 is a potential antipsychotic that displays agonist and antagonist p roperties at serotonin (5-HT)(1A) and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increase d punished responses, an action mimicked by S-16924, whereas the atypical a ntipsychotic clozapine and the neuroleptic haloperidol were inactive. Simil arly, in a Vogel conflict paradigm in rats, CLZ increased punished response s, an action shared by S-16924 but not by clozapine or haloperidol. This ac tion of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultraso nic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and ha loperidol. However, although WAY-100,635 abolished the action of S-16924, i t did not affect clozapine and haloperidol. In a rat elevated plus-maze, CL Z, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924 . CLZ, S-16924, clozapine, and haloperidol decreased aggressive interaction s in isolated mice, but this effect of S-16924 was not blocked by WAY-100,6 35. All drugs inhibited motor behavior, but the separation to anxiolytic do ses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialys is levels of 5-HT in the nucleus accumbens: this action of S-16924 was bloc ked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine , S-16924 possessed a broad-based profile of anxiolytic activity at doses l ower than those provoking motor disruption. Its principal mechanism of acti on was activation of 5-HT1A (auto)receptors.