HIGH-AFFINITY BENZODIAZEPINE ANTAGONISTS REDUCE RESPONDING MAINTAINEDBY ETHANOL PRESENTATION IN ETHANOL-PREFERRING RATS

In the present study, we examined two high-affinity and selective benz odiazepine (BDZ) receptor antagonists (ZK 93426, CGS 8216) in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was mai ntained by the presentation of EtOH. The in vivo actions of CGS 8216 ( 1-30 mg/kg) and ZK 93426 (5-75 mg/kg) were examined after intraperiton eal or oral administration. Flumazenil (10-40 mg/kg) was used as a ref erence BDZ antagonist. EtOH (10% v/v) and saccharin (0.05 g/v) solutio ns were concurrently available for 30 min each day under a two-lever f ixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the sacch arin solution. A 40 mg/kg intraperitoneal injection of flumazenil give n on the first injection day (day 1) nonsignificantly reduced control levels of responding maintained by EtOH by 36%. No effects were observ ed 24 hr after drug administration (day 2). Oral administration of flu mazenil was without effect. On day 1, intraperitoneal administration o f CGS 8216 (1-20 mg/kg) and ZK 93426 (1-50 mg/kg) reduced control leve ls of responding maintained by ROH by 44% to 73%; on day 2, EtOH maint ained responding continued to be suppressed with the highest doses (gr eater than or equal to 20 mg/kg) suppressing control levels of respond ing by as much as 62%. Oral administration of higher doses of CGS 8216 (5-30 mg/kg) and ZK 93426 (10-75 mg/kg) reduced responding maintained by ROH by as much as 54% to 84% of controls; however, no effects were seen on day 2. Only the highest intraperitoneal dose of ZK 93426 (50 mg/kg) suppressed responding maintained by saccharin. These findings d emonstrate that some BDZ antagonists decrease responding maintained by EtOH. The findings suggest that certain BDZ antagonists may have pote ntial as pharmacotherapies to prevent or decrease EtOH abuse in humans .