Antagonism of ethanol effects on cerebellar Purkinje neurons by the benzodiazepine inverse agonists RO 15-4513 and FG 7142: Electrophysiological studies

Ro 15-4513, a benzodiazepine inverse agonist, has been reported to antagonize the ataxic effects of ethanol. The present study investigates the Ro 15-4513 sensitivity of rat cerebellar Purkinje neurons to the depressant effects of locally applied ethanol. Local applications of ethanol by pressure ejection from multibarrel micropipettes caused reversible and dose-dependent depressions of the neuronal firing rates of single cerebellar Purkinje neurons. The ethanol-induced depressions could be antagonized by local applications of Ro 15-4513 applied from another barrel of the same micropipette. This antagonism was not competitive, suggesting that Ro 15-4513 does not interfere directly with the initial step of the ethanol mechanism of action. A β-carboline inverse agonist, FG 7142, was more efficacious than Ro 15-4513 for antagonizing the ethanol-induced depressions, but appeared to be less potent. Recovery of ethanol-induced depressions of Purkinje neurons firing rates after Ro 15-4513 antagonism was not usually observed for 1 hr or more after the antagonist application. In contrast to ethanol effects, qualitatively similar γ-aminobutyric acid-induced depressions of these same neurons were not antagonized by the doses of Ro 15-4513 used. We conclude that the electrophysiological depressant effects of ethanol on cerebellar neuronal activity can be antagonized by the benzodiazepine inverse agonists, Ro 15-4513 and FG 7142.