Vol. 284, Issue 3, 1006-1014, March 1998

High-Affinity Benzodiazepine Antagonists Reduce Responding Maintained by Ethanol Presentation in Ethanol-Preferring Rats¹

Harry L. June , Dana Zuccarelli, Lucas Torres, Karen S. Craig, Jana Delong, Angela Allen, Misty R. Braun, Charity R. Cason and James M. Murphy

Department of Psychology (H.L.J, D.Z., L.T., K.S.C, J.D., A.A., M.R.B., C.R.C., J.M.M), Purdue School of Science, and Institute of Psychiatric Research and Program in Medical Neurobiology (H.L.J, J.M.M), Department of Psychiatry, Indiana University School of Medicine, Indiana University-Purdue University, Indianapolis, Indiana

In the present study, we examined two high-affinity and selective benzodiazepine (BDZ) receptor antagonists (ZK 93426, CGS 8216) in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained 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 intraperitoneal or oral administration. Flumazenil (10-40 mg/kg) was used as a reference BDZ antagonist. EtOH (10% v/v) and saccharin (0.05 g/v) solutions were concurrently available for 30 min each day under a two-lever fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. A 40 mg/kg intraperitoneal injection of flumazenil given on the first injection day (day 1) nonsignificantly reduced control levels of responding maintained by EtOH by 36%. No effects were observed 24 hr after drug administration (day 2). Oral administration of flumazenil was without effect. On day 1, intraperitoneal administration of CGS 8216 (1-20 mg/kg) and ZK 93426 (1-50 mg/kg) reduced control levels of responding maintained by EtOH by 44% to 73%; on day 2, EtOH maintained responding continued to be suppressed with the highest doses (20 mg/kg) suppressing control levels of responding 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 EtOH 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 demonstrate that some BDZ antagonists decrease responding maintained by EtOH. The findings suggest that certain BDZ antagonists may have potential as pharmacotherapies to prevent or decrease EtOH abuse in humans.