GABA antagonist and benzodiazepine partial inverse agonist reduce motivated responding for ethanol

Brain gamma-aminobutyric acid (GABA) systems have long been associated with the behavioral actions of ethanol. This study investigated the effects of GABAergic agents on ethanol reinforcement. Rats were trained to orally self-administer ethanol in a 30-min, free-choice operant task. Responses at one of two levers produced contingent access to ethanol (10% w/v) or water. Pretreatment with RO 15-4513, a benzodiazepine inverse agonist (0.375 to 3.0 mg/kg ip), selectively reduced responses for ethanol, and a higher dose of RO 15-4513 (6.0 mg/kg) reduced both ethanol and water responses. Self-administration of saccharin in a free-choice task with access to saccharin (0.05%) and water was unaffected by RO 15-4513, suggesting that the effects of RO 15-4513 on ethanol reinforcement may not necessarily generalize to other reinforcers. Isopropylbicyclophosphate (IPPO), a picrotoxin ligand (5 and 10 micrograms/kg ip), selectively reduced responses for ethanol in alcohol-preferring, nonpreferring and Wistar rats. However, the highest dose of IPPO (20 micrograms/kg) reduced both ethanol and water responses. Chlordiazepoxide, a benzodiazepine, did not reduce responses for ethanol in the selectively bred animals, suggesting that this drug does not substitute for the reinforcing properties associated with acute ethanol intake. Together, these results suggest that compounds that act at the benzodiazepine inverse agonist and picrotoxin sites of the GABA/benzodiazepine receptor complex may decrease motivated responding for ethanol.