Effects of the 5HT(1A) agonist anxiolytic gepirone on benzodiazepine withdrawal signs in rats.

The effects of gepirone at 3, 9 and 27mg/kg (b.i.d.) on benzodiazepine (BZ) withdrawal signs were studied in rats pretreated with chlordiazepoxide for 21 days at doses up to 40mg/kg b.i.d. The BZ withdrawal indices studied were weight loss and anorexia. At 9 and 27, but not 3mg/kg (b.i.d.) gepirone potentiated the weight loss and anorexia seen during BZ withdrawal. These effects could not be attributed simply to high dose drug-induced "malaise" inhibiting food intake, since in drug-naive animals gepirone stimulated food intake and increased bodyweight. These data show clearly that gepirone potentiates BZ withdrawal signs. Similar findings have been reported recently in studies with ipsapirone (Goudie and Leathley, 1991). Such effects could be mediated by the a(2)-adrenoceptor antagonist actions of 1-(2-pyrimidinyl)piperazine (1-PP), an active metabolite of both gepirone and ipsapirone. Such findings may explain why prior BZ experience impairs the clinical response to buspirone-type anxiolytics acting at the 5-HT(1A) receptor.