Withdrawal from ingested diazepam produces a pentylenetetrazol‐like stimulus in rats

AbstractAn interoceptive stimulus produced by withdrawal from chronic diazepam is similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). Because the PTZ stimulus can be measured objectively in animals, its use was proposed as a bioassay for diazepam‐withdrawal stimuli. In previous studies, diazepam was given chronically by the intraperitoneal route. The purpose of the present study was to determine whether withdrawal from diazepam given in the diet would similarly produce a PTZ‐like subjective effect. Administering drug through the diet has the advantage that it eliminates the necessity of giving injections every 6–8 hr and more closely parallels human chronic dosing. Rats were trained with food‐reward in a two‐lever operant task. Presses on one lever were reinforced after injections of PTZ, 20 mg/kg, and on the other lever after saline. After rats had acquired the PTZ discrimination, training was halted, and they were given diazepam, 240 mg/kg/day, in a nutritionally complete liquid diet. Withdrawal was precipitated after 3 or 4 days of chronic diazepam with the benzodiazepine receptor blocker Ro 15–1788, either after a bolus dose of diazepam, given intraperitoneally, or during continued dietary diazepam. During precipitated withdrawal, the rats selected the PTZ lever, indicating the presence of a PTZ‐like stimulus, and this stimulus was blocked by phenobarbital, 80 mg/kg. The percentage of rats selecting the PTZ lever depended on the dose of Ro 15–1788. By 3.5 days after cessation of chronic diazepam, Ro 15–1788 no longer produced a PTZ‐like stimulus and by 11 days, rats recovered baseline discrimination performance, as indicated by saline‐lever selection after saline injections and PTZ‐lever selection after PTZ. These data indicate that a subjective effect of withdrawal similar to that obtained after parenteral diazepam can be produced after chronic diazepam given daily in the diet.