Abstract

Rats were trained to discriminate pentylenetetrazol (PTZ, an anxiogenic drug), 20.0 mg/kg, from saline using a food-maintained two-lever-choice task. When treated chronically with diazepam (DZP) and tested with the benzodiazepine-receptor antagonist Ro 15-1788, withdrawal from DZP produced a PTZ-like stimulus in these subjects that was related directly to the dose of DZP given every 8 hr for 6 days. In contrast, only the highest dose of DZP (80 mg/kg/8 hr) given chronically produced even minimal physical signs of precipitated abstinence after Ro 15-1788. In a separate experiment, Ro 15-1788 produced a PTZ-like stimulus when given at 2-day intervals during chronic administration of DZP. In this experiment, rats were maintained on DZP, 40.0 mg/kg/6 hr for 14 days. These subjects were tested with Ro 15-1788, 40.0 mg/kg, every 2 days during days 6 through 14 of chronic DZP, and Ro 15-1788 substituted for PTZ on 4 of these 5 tests. Because these experiments involved periods of nontraining on the discrimination task, a final experiment was performed to test the stability of stimulus control in rats trained to detect PTZ. DZP was administered for up to 20 days, withdrawal was precipitated by Ro 15-1788 and after an additional 16 to 40 days of nontraining, stimulus control was tested. There was no significant decline in stimulus control over this period. These results suggest that PTZ discrimination provides a sensitive, stable assay for the detection of withdrawal from benzodiazepine dependence.