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[a putative non-benzodiazepine (BZ) anxiolytic] and chlordiazepoxide (CDP); and ii) effects of ipsapirone in animals withdrawn from CDP.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 wasnot 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 didnot 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”. The most plausible account of the observed potentiation of withdrawal by ipsapirone involves actions of the ipsapirone metabolite (1-(2-pyrimidinyl)-piperazine) on alpha2-adrenoceptors, which are known to be implicated in BZ withdrawal. However, the precise mechanism involved remains unclear. Collectively, the studies reported show that ipsapirone does not induce the type of withdrawal signs seen with BZs. However, there was no evidence that ipsapirone attenuated BZ withdrawal. It is therefore likely that patients withdrawn from BZs will experience withdrawal if treated with ipsapirone, and that if treated with high doses withdrawal may be exacerbated.
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An abstract report of some of the data reported here has been published previously (Goudie A.J., Leathley M., McNally J. (1989a))
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Goudie, A.J., Leathley, M.J. Evaluation of the dependence potential of the selective 5-H1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal. Psychopharmacology 103, 529–537 (1991). https://doi.org/10.1007/BF02244254
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DOI: https://doi.org/10.1007/BF02244254