Selective changes in sensitivity to benzodiazepines, and not other positive GABA_A modulators, in rats receiving flunitrazepam chronically

Rationale: Tolerance and dependence can develop during chronic benzodiazepine treatment; however, cross tolerance and cross dependence to positive modulators acting at other sites on GABA_A receptors might not occur. Objectives: The current study evaluated changes in sensitivity to positive GABA_A modulators during chronic treatment with the benzodiazepine flunitrazepam to determine whether cross tolerance and cross dependence varied as a function of site of action. Methods: Eight rats responded under a fixed ratio 20 schedule of food presentation. Dose-effect curves were determined before, during and after chronic treatment with one or two daily injections of 1 mg/kg of flunitrazepam. Results: Prior to chronic treatment, benzodiazepines (flunitrazepam, midazolam), a barbiturate (pentobarbital), a neuroactive steroid (pregnanolone), and drugs with primary mechanisms of action at receptors other than GABA_A receptors (morphine, ketamine) dose-dependently decreased responding. Twice daily treatment with flunitrazepam produced 9.5- and 23-fold shifts to the right in the flunitrazepam and midazolam dose-effect curves, respectively. In contrast, dose-effect curves for other drugs either were not changed or were shifted less than or equal to fourfold to the right. Conclusions: Decreased sensitivity to benzodiazepines and not to a barbiturate or a neuroactive steroid during chronic flunitrazepam treatment indicates that tolerance and cross tolerance developed only to benzodiazepines. Despite similar acute behavioral effects among positive GABA_A modulators, the differential development of cross tolerance suggests that adaptations at GABA_A receptors produced by chronic benzodiazepine treatment differentially affect positive modulators depending on their site of action; such differences might be exploited to benefit patients treated daily with positive GABA_A modulators.