PT  - JOURNAL ARTICLE
AU  - Millan, Mark J.
AU  - Brocco, Mauricette
AU  - Gobert, Alain
AU  - Schreiber, Rudy
AU  - Dekeyne, Anne
TI  - S-16924 [(<em>R</em>)-2-{1-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl}-1-(4-fluorophenyl)-ethanone], a Novel, Potential Antipsychotic with Marked Serotonin<sub>1A</sub>Agonist Properties: III. Anxiolytic Actions in Comparison with  Clozapine and Haloperidol
DP  - 1999 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1002--1014
VI  - 288
IP  - 3
4099  - http://jpet.aspetjournals.org/content/288/3/1002.short
4100  - http://jpet.aspetjournals.org/content/288/3/1002.full
SO  - J Pharmacol Exp Ther1999 Mar 01; 288
AB  - S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, 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 interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100,635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors. The American Society for Pharmacology and Experimental Therapeutics