Functional alterations in cerebral GABAA receptor complex associated with formation of alcohol dependence: analysis using GABA-dependent 36Cl- influx into neuronal membrane vesicles.

The effect of alcohol dependence induced by ethanol inhalation on GABA-dependent 36Cl- influx into membrane vesicles prepared from the mouse brain has been examined. Ethanol, flunitrazepam and salsolinol induced a significant facilitation of the GABA-dependent 36Cl- influx into membrane vesicles obtained from the normal mouse brain. Ethanol inhalation induced the facilitation of GABA-dependent 36Cl- influx at 3-12 hr after the initiation of inhalation, but this facilitation returned to a normal level within 12 hr. In membrane vesicles obtained from the brain of an alcohol-dependent mouse at 7 days after the initiation of ethanol inhalation, not only was there a significant decrease of the GABA-dependent 36Cl- influx but there occurred also the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx. This decrease in GABA-dependent 36Cl- influx was found to be recovered within 8 hr after the withdrawal of ethanol inhalation. On the other hand, behavioural withdrawal signs such as tonic-clonic convulsions with grimaces and heads thrown back appeared at 8 hr after the withdrawal of ethanol inhalation and continued for 8-16 hr. These results suggest that the observed functional deteriorations at cerebral GABAA receptors such as the decrease of GABA-dependent 36Cl- influx and the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx may contribute to the preparation of the exhibition of ethanol withdrawal signs and/or the establishment of functional tolerance to alcohol, but are not directly related to the exhibition of alcohol withdrawal signs.