Differential regulation of the behavioral effects of chlordiazepoxide

Chronic administration of the benzodiazepine (BZ) receptor agonist chlordiazepoxide (CDP) produced tolerance to its motor-impairing effects but little or no tolerance to its hypothermic effects or to its amnesic effects in the radial arm maze. Male Sprague-Dawley rats were pretreated for 14 days with CDP (25 mg/kg, b.i.d., IP) or saline, and chronic treatment was maintained throughout the experiments. Tolerance was evaluated by constructing dose-response curves to CDP following chronic administration of either CDP or saline. Tolerance developed to only certain behavioral effects of CDP. Tolerance developed to the motor-impairing effects of CDP as assessed in three different procedures: rotarod, spontaneous locomotor activity, and acquisition of the step-through inhibitory avoidance response. In contrast, tolerance did not develop to the hypothermic effects of CDP. Tolerance to the amnesic effects of CDP was contingent upon the behavioral procedure. For example, tolerance developed to reductions of retention latency in the step-through inhibitory avoidance response, but not to impairment of the acquisition of radial arm maze performance. These results are consistent with the effects of chronic BZ administration in humans and demonstrate a parallel regulation of drug effects, potentially mediated by regional differences in BZ receptor subtype regulation or composition.