PROTRACTED WITHDRAWAL - SENSITIZATION OF THE ANXIOGENIC RESPONSE TO COCAINE IN RATS CONCURRENTLY TREATED WITH ETHANOL

Rats were trained to respond on one lever following an injection of saline and the alternate lever after the anxiogenic drug pentylenetetrazol (PTZ 20 mg/kg), according to a fixed ratio (FR10) schedule of food reinforcement. The trained animals were then administered dependence-producing regimens of either cocaine (20 mg/kg, [IP], three times daily for 7 days) or ethanol (mixed 4.5% w/v with sweetened liquid diet given for 5 days). Separate groups of trained rats were given either subthreshold regimens of cocaine (20 mg/kg, IP, three times daily for 5 days), ethanol (2.25% w/v of the diet given for 5 days), or both. Additional groups were matched for control groups. After discontinuation of these regimens, rats were administered test injections of either saline or cocaine, and tested for elicitation of the PTZ-stimulus at selected intervals of withdrawal. After a saline injection, maximum elicitation of the PTZ-stimulus was observed 12 hours following chronic treatment with the higher dose of ethanol, and 120 hours following longer treatment with cocaine. During those periods of withdrawal when a saline injection failed to produce a PTZ-like stimulus, a test injection of cocaine (10 mg/kg) elicited the PTZ-stimulus in the ethanol withdrawn rats, although only partially eliciting the PTZ-stimulus in the cocaine withdrawn group. In the pair-fed controls, or rats withdrawn from the smaller dosage of either ethanol or cocaine, the test dose of saline or cocaine did not elicit the PTZ-stimulus; only 30% of rats selected the PTZ-appropriate lever at the highest dose of cocaine tested (10 mg/kg). In contrast, cocaine fully elicited the PTZ-stimulus in animals withdrawn from the combination of cocaine and ethanol, with over 85% of the rats selecting the PTZ lever following the test injection of cocaine (10 mg/kg), but not saline. This anxiogenic response to cocaine occurred following doses and durations of cocaine or ethanol that were incapable of producing the cocaine-induced elicitation of the PTZ-stimulus when administered alone. These results indicate that repeated and simultaneous administration of ethanol with cocaine enhances the anxiogenic response to cocaine during the protracted withdrawal period.