Evaluation of the dependence potential of the selective 5-H1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal

Abstract

Two initial studies investigated: i) the effects of withdrawal from ipsapirone [a putative non-benzodiazepine (BZ) anxiolytic] and chlordiazepoxide (CDP); and ii) effects of ipsapirone in animals withdrawn from CDP. Rats were injected b.i.d. for 21 days with saline, ipsapirone or CDP at doses up to 40 mg/kg/injection. Subsequently, controls received the treatment administered previously, other subjects received saline during withdrawal from ipsapirone or CDP. Further subjects received ipsapirone (3, 10 or 30 mg/kg b.i.d.) during CDP withdrawal. Withdrawal indices recorded were body weight and food intake. Withdrawal signs were absent after ipsapirone treatment but present after CDP treatment, when food intake and bodyweight measures fell and then recovered. At the high dose of 30 mg/kg (b.i.d.) ipsapirone potentiated CDP withdrawal signs. Potentiation of withdrawal was not seen in animals treated with ipsapirone at lower doses (3 and 10 mg/kg, b.i.d.). In a subsequent study we found that ipsapirone conditioned a taste aversion, a possible index of drug-induced "malaise", at doses as low as 7.5 mg/kg. Therefore a possible explanation for the potentiation of BZ withdrawal in subjects treated with high doses of ipsapirone was that drug-induced "malaise" reduced food intake and body weight, rather than ipsapirone causing true potentiation of BZ withdrawal. However, in a further study we showed that the ipsapirone treatment regime which potentiated BZ withdrawal did not significantly reduce food intake or body weight, suggesting that high doses of ipsapirone potentiate BZ withdrawal by a mechanism that does not simply involve "malaise".(ABSTRACT TRUNCATED AT 250 WORDS)