beta CCT as well as flumazenil prevent the diazepam withdrawal-induced anxiety in the elevated plus maze in rats

Abstract

Objective : Despite a half century of clinical use and the recognized potential of benzodiazepine dependence, the mechanisms under- lying benzodiazepine withdrawal remain insufficiently understood. The aim of the present study was to assess the influence of the non- selective antagonist (flumazenil) and the preferential a1-subunit selective antagonist (bCCt) on the anxiety level after diazepam with- drawal. Methods : The male Wistar rats were protractedly treated during 21 days with diazepam (2 mg/kg) or solvent. On the testing day, 24 hours after the last injection, animals from the diazepam-treated groups received either antagonist (flumazenil or bCCt) or solvent, and animals from the solvent-treated groups received solvent or diaze- pam. Twenty minutes after administration of treatment on the testing day, single animals were placed in the elevated plus maze in order to assess the level of anxiety. Results : Two-way ANOVA revealed that animals withdrawn from diazepam spent significantly less time on the open arms than control animals (p=0.023). One-way ANOVA, followed by post hoc test, re- vealed that administration of flumazenil (10 mg/kg) or bCCt (1.25, 5 or 20 mg/kg) reversed the diazepam withdrawal-induced anxiety (percentage of open arm time : p=0.003, p=0.032, p=0.031 and p=0.014 compared to the diazepam-withdrawn group, respectively). Concomitant administration of antagonists (10 mg/kg flumazenil, or 1.25, 5 or 20 mg/kg bCCt) induced an anxiolytic effect comparable to that observed after acutely administrated diazepam (percentage of open arm time : p=0.142, p=0.187, p=0.243 and p=0.290, respect- ively). Conclusion : The present study demonstrated that administration of the a1-selective antagonist bCCt or non-selective antagonist flumazenil could prevent the withdrawal-induced anxiety and also induce an anxiolytic-like effect. Moreover, presented results have suggested that mechanism of preventing the withdrawal-induced anxiety involves the antagonism at a1-containing GABAA receptors.