DIFFERENTIAL REGULATION OF THE BEHAVIORAL-EFFECTS OF CHLORDIAZEPOXIDE

Chronic administration of the benzodiazepine (BZ) receptor agonist chl ordiazepoxide (CDP) produced tolerance to its motor-impairing effects but little or no tolerance to its hypothermic effects or to its amnesi c effects in the radial arm maze. Male Sprague-Dawley rats were pretre ated for 14 days with CDP (25 mg/kg, b.i.d., IF) or saline, and chroni c treatment was maintained throughout the experiments. Tolerance was e valuated by constructing dose-response curves to CDP following chronic administration of either CDP or saline. Tolerance developed to only c ertain behavioral effects of CDP. Tolerance developed to the motor-imp airing effects of CDP as assessed in three different procedures: rotar od, spontaneous locomotor activity, and acquisition of the step-throug h inhibitory avoidance response. In contrast, tolerance did not develo p to the hypothermic effects of CDP. Tolerance to the amnesic effects of CDP was contingent upon the behavioral procedure. For example, tole rance developed to reductions of retention latency in the step-through inhibitory avoidance response, but not to impairment of the acquisiti on of radial arm maze performance. These results are consistent with t he effects of chronic BZ administration in humans and demonstrate a pa rallel regulation of drug effects, potentially mediated by regional di fferences in BZ receptor subtype regulation or composition.