Actions of ritanserin, a 5-HT2/1C antagonist, in benzodiazepine-dependent rats

Abstract

The effects of ritanserin on spontaneous benzodiazepine (BZ) withdrawal-induced weight loss, anorexia and hypodipsia were studied. Groups of female rats initially received i.p. injections b.i.d. (11.00 and 17.00h) of either saline or chlordiazepoxide (CDP). CDP doses increased by 2mg/kg/day from 10mg/kg to a final does of 30mg/kg. Treatment was maintained for 26 days. Over the next 6 days animals were either treated b.i.d. with vehicle, CDP, or ritanserin at one of three doses (0.16,0.63 and 2.5mg/kg). In CDP-pretreated animals subsequently treated with vehicle, significant weight loss, anorexia and hypodipsia were seen, relative to controls. In saline-pretreated animals ritanserin had no effect on body weight. However, CDP withdrawal-induced weight loss was actually exacerbated by ritanserin, in a dose-related fashion. Thus, ritanserin potentiated withdrawal-induced weight loss, by a process which did not involve functional (additive) effects of withdrawal and ritanserin treatment. Ritanserin stimulated food intake in saline-pretreated animals. Despite this effect it failed to alleviate CDP withdrawal-induced anorexia. However, in contrast to the weight loss index, no evidence was obtained for potentiation of withdrawal-induced anorexia. In saline-pretreated animals ritanserin had no effect on water intake, nor did it alleviate or potentiate CDP withdrawal-hypodipsia. Thus the effects of ritanserin on somatic BZ withdrawal signs depended upon the specific sign studied, different signs showing potentiation or no effect. However, for none of the signs studied was there any evidence that ritanserin alleviated the effect of CDP withdrawal. 5-HT(2/1C) antagonists may therefore be of limited value in the treatment of somatic aspects of the BZ withdrawal syndrome. They may even exacerbate some BZ withdrawal signs, although a full characterization of the effects of such drugs on BZ withdrawal requires that a number of other different withdrawal signs and symptoms should be studied, since it seems likely that different BZ withdrawal signs involve different underlying mechanisms.