DIFFERENTIAL TOLERANCE TO THE EFFECTS OF CHLORDIAZEPOXIDE ON UNPUNISHED AND PUNISHED OPERANT RESPONDING FOLLOWING CHRONIC TREATMENT

Differential development of tolerance to the effects of benzodiazepine s (BZs) is a common clinical phenomenon. To examine whether the develo pment of tolerance to the response-suppressant and antipunishment effe cts of BZs were differentially regulated in animals, male Sprague-Dawl ey rats were treated chronically with either the BZ receptor agonist c hlordiazepoxide (CDP, 25 mg/kg, IP, b.i.d.) or saline for 15 weeks and examined under a multiple schedule of operant behavior. Chronic admin istration of CDP produced tolerance to its suppressive effects on unpu nished responding (RI 80 s) but no tolerance to its enhancing effects on punished responding. This conclusion is supported by three observat ions. First, repeated priming with CDP produced tolerance to its respo nse-suppressive effects in the RI 80-s schedule and revealed increases in punished responding. Second, baseline levels for punished respondi ng remained elevated over the 15-week treatment period. Third, toleran ce developed to the response-suppressant effects of CDP under the RI 8 0-s schedule, as indicated by a sixfold shift to the right in the dose -response curves for rats treated chronically with CDP when compared t o saline-treated controls. However, tolerance did not develop to the a ntipunishment effects of CDP, as indicated by no differences in the do se-response curves for punished responding. Discontinuation of chronic treatment disrupted unpunished responding only on the first day, and reversed the increase in punished responding. Taken together, these re sults indicate that differential regulation occurs for the development of tolerance to the response-suppressant and antipunishment effects o f BZs.