Gender Differences in Diazepam Withdrawal Syndrome in Mice

Abstract

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.

The effects of midazolam and flumazenil on psychomotor function and alertness in human volunteers

“…Sedated subjects given flumazenil had significantly improved alertness when compared with those given saline as described by other investigators. 18 At 60 minutes, alertness was not significantly different from the control group.…”

“…Interestingly there is evidence in the literature that the mechanism of action of benzodiazepines is modulated by the action of sexual hormones and that testosterone plays a relevant role. 18 It has been suggested that the elimination half-lives of benzodiazepines do not necessarily correspond with their sedative pharmacodynamic effects 19 and this has lead some to advocate continuous infusion of flumazenil for 2 hours to ensure that patients are free from resedation following induction of anaesthesia with midazolam. 20 Certainly after the smaller doses required for conscious sedation, there is no evidence that this is required.…”

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance

“…There is suggestive evidence derived from preclinical and clinical experiments (e.g., Stock et al 1999) that the ovarian hormones (estrogen and/or progesterone) cause more intense withdrawal reactions in chronically BZP treated rodents Biscardi 1992, 1993;Wilson et al 1996). Conversely, male hormones have been shown to inhibit these reactions (Pesce et al 1994;Pires et al 1998). These studies were limited to full-blown withdrawal reactions and thus their relevance to the subtle sex-related differences in cortisol elevations in the present study is not known.…”

“…The basis for the increased use of BZPs among elderly women is not well understood and may involve sociocultural factors as well as sex differences in the prevalence of disorders for which BZPs are commonly prescribed. In addition, there are several sex-related biological factors that may result in females having more intense BZP withdrawal reactions (Pesce et al 1994), which were associated with failure to successfully discontinue BZP use. For example, experiments in rodents have demonstrated that the ovarian hormones, estrogen and/or progesterone, increase the intensity of withdrawal reactions in chronically BZP-treated animals Biscardi 1992, 1993).…”

Progesterone and Testosterone Modulate the Convulsant Actions of Pentylenetetrazol and Strychnine in Mice

“…Box 442, Correo 2, Santiago, Chile (fax π56 2 681 9052). levels are high, than in dioestrus (Pesce et al 1994(Pesce et al & 1996. The present work was designed to evaluate the influence of progesterone and testosterone on the convulsivant effects of pentylenetetrazol and strychnine.…”