Gender differences in diazepam withdrawal syndrome in mice

The present work was designed to study the influence of testosterone and oestrogens on the benzodiazepine withdrawal syndrome in mice. Several withdrawal signs were induced by 15 mg/kg intraperitoneally of flumazenil in diazepam-treated mice. The most noticeable were jerks, usually accompanied by tail lifts, and seizures. The intensity of the diazepam withdrawal syndrome was significantly lower in male than in female mice, especially in relation to the incidence of seizures. Castrated male mice showed a significant increase in the intensity of withdrawal syndrome. In addition, diazepam produced a significant increase of body weight in males but not in females. The principal finding of the present work is that the incidence of seizures produced by the administration of flumazenil was significantly lower in male than in female diazepam-treated mice. This fact suggests that the mechanism of action of benzodiazepines is modulated by the action of sexual hormones, and that testosterone plays a relevant role.