Abstract
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 vivoactions 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.
Footnotes
-
Send reprint requests to: Harry L. June, Ph.D., Department of Psychology, LD 124, IUPUI, 402 North Blackford Street, Indianapolis, IN 46202-3275. E-mail:hjune{at}iupui.edu
-
↵1 This research was supported in part by Grants AA10717 and AA07611 from National Institute of Alcohal Abuse and Alcohalism. Portions of this research were presented in part at the Annual Meeting of the Research Society on Alcoholism, Washington, D.C., June 1996. D.Z. and L.T. were supported in part by the Indiana University-Purdue University, Indianapolis, Department of Psychology (SPUR) and Undergraduate Mentorship Fellowship from the Office of Faculty Development. L.T. and C.R.C. were supported in part by Grant T35 M from the National Heart, Lung, and Blood Institute, National Institutes of Health Training Program for Minority Students in Biomedical Research.
- Abbreviations:
- EtOH
- ethanol
- BDZ
- benzodiazepine
- GABA
- γ-aminobutyric acid
- GABAA
- γ-aminobutyric acid type A
- P
- ethanol-preferring rats
- FR
- fixed-ratio
- ANOVA
- analysis of variance
- i.p.
- intraperitoneal
- BAC
- blood alcohol concentration
- Received December 24, 1996.
- Accepted November 28, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|