Differential regulation of the behavioral effects of chlordiazepoxide
Differential development of tolerance to the effects of benzodiazepines (BZs) is a common clinical phenomenon. Patients who are treated chronically with BZs develop rapid tolerance to the anticonvulsant and sedative effects, but not to the anti-anxiety or amnesic effects. To examine whether the development of tolerance to the behavioral effects of a single BZ, chlordiazepoxide (CDP), was differentially regulated in animals, male Sprague-Dawley rats were pretreated for 14 days with 25 mg/kg CDP (IP, b.i.d.) or saline. Chronic treatment was maintained throughout the experiments. Tolerance was evaluated by comparing CDP dose-response curves between groups in a variety of behavioral procedures. The motor-impairing effects of CDP were assessed in three different procedures: rotarod, spontaneous locomotor activity, and acquisition of the step-through inhibitory avoidance response. Hypothermic responses were measured by changes in rectal temperature. Amnesic effects were measured in the inhibitory avoidance procedure and the radial arm maze. Antipunishment effects were measured in a multiple schedule of operant responding with unpunished (RI 80-sec) and punished (CRF with incremental shock intensities) components. These procedures permitted simultaneous measurement of motor-impairing effects with either amnesic or anxiolytic effects. Chronic administration of CDP produced tolerance to its motor-impairing effects but not to its hypothermic, amnesic, or antipunishment effects. 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. Tolerance to the effects of CDP on operant responding was schedule-dependent. Tolerance developed to the response-suppressant effects on RI 80-sec responding. Conversely, tolerance did not develop to the enhancing effects of CDP on punished responding. In addition, baseline levels for punished responding over the 15-week treatment period remained elevated, suggesting that tolerance did not develop to this drug effect. 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.
Shumsky, Jed Steven, "Differential regulation of the behavioral effects of chlordiazepoxide" (1993). Dissertations available from ProQuest. AAI9413909.