BENZODIAZEPINE RECEPTOR ANTAGONISTS MODULATE THE ACTIONS OF ETHANOL IN ALCOHOL-PREFERRING AND ALCOHOL-NONPREFERRING RATS

The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5 H)-one, 0.05-2 mg/kg) and the beta-carboline ZK 93426 5-isopropyl-4-me thyl-beta-carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavio ral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice t est between ethanol (10% v/v) and a saccharin (0.0125% g/v) solution, both antagonists dose-dependently reduced intake of ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of the 4 h l imited access. Saccharin drinking was suppressed only with the highest doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxi olytic effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the pl us maze test in alcohol-preferring rats, but potentiated the ethanol-i nduced suppression in alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg ) and ZK 93426 (4 mg/kg) attenuated the ethanol (0.5 and 1.5 g/kg)-ind uced suppression in the open field in alcohol-nonpreferring rats; howe ver, CGS 8216 potentiated the depressant effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These findings provide evi dence that benzodiazepine receptor antagonists may differentially modu late the behavioral actions of ethanol in alcohol-preferring and-nonpr eferring rats. It is possible that the qualitative pharmacodynamic dif ferences seen in the present study may be related to selective breedin g for alcohol preference. The findings indicate the potential for deve lopment of receptor specific ligands devoid of toxic effects which may be useful in the treatment of alcohol abuse and alcoholism. (C) 1998 Elsevier Science B.V.