Tolerance liability of diazepam is dependent on the dose used for protracted treatment

Abstract

Background: Behavioral effects of benzodiazepines following repeated exposure vary according to the intrinsic efficacy of the benzodiazepine studied, treatment schedule and the behavioral parameters evaluated. Methods: We applied the behavioral paradigms of spontaneous locomotor activity, elevated plus maze and grip strength to investigate the sedative, anxiolyfic and myorelaxant effect of acute challenge with 2 mg/kg diazepam administered after 14 days of protracted treatment with 0.5, 2 or 10 mg/kg of diazepam. In addition, we studied the effects of everyday handling and intraperitoneal (ip) administration on animal behavior. Results: Tolerance to the sedative effect of 2 mg/kg diszepam ensued after 14 days of protracted treatment with 2 and 10 mg/kg of diazepam. In contrast, treatment with the lowest dose (0.5 mg/kg) of diazepam resulted in potentiation of the sedative effect of acute challenge with 2 mg/kg diazepam thus confounding the detection of the anxiolytic effect of diazepam. A sensitization-like response to the anxiolytic action of 2 mg/kg diazepam was seen after protracted treatment with the intermediate dose (2 mg/kg); however, anxiolytic effect was absent after protracted administration of the highest dose. Partial tolerance to the muscle relaxant effect of 2 mg/kg diazepam ensued after protracted treatment with diazepam regardless of the dose. Daily handling or ip administration did not alter the behavioral response to acute challenge with 2 mg/kg diazepam in all the three behavioral paradigms studied. Conclusion: The presented results showed that behavioral effects of acute challenge with diazepam were differently affected by the dose administered during protracted treatment.