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

Abstract

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. 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. 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. 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. 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.