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Flumazenil selectively prevents the increase in α4‐subunit gene expression and an associated change in GABAA receptor function induced by ethanol withdrawal

The actions of ethanol on γ‐aminobutyric acid type A (GABAA) receptors are still highly controversial issues but it appears that some of its pharmacological effects may depend on receptor subunit composition. Prolonged ethanol exposure produces tolerance and dependence and its withdrawal alters GABAA receptor subunit gene expression and function. Whereas benzodiazepines are clinically effective in ameliorating ethanol withdrawal symptoms, work in our laboratory showed that benzodiazepines also prevent, in vitro, some of the ethanol withdrawal‐induced molecular and functional changes of the GABAA receptors. In the present work, we investigated the effects, on such changes, of the benzodiazepine receptor antagonist flumazenil that can positively modulate α4‐containing receptors. We here report that flumazenil prevented both the ethanol withdrawal‐induced up‐regulation of the α4‐subunit and the increase in its own modulatory action. In contrast, flumazenil did not inhibit ethanol withdrawal‐induced decrease in α1‐ and δ‐subunit expression as well as the corresponding decrease in the modulatory action on GABAA receptor function of both the α1‐selective ligand zaleplon and the δ‐containing receptor preferentially acting steroid allopregnanolone. These observations are the first molecular and functional evidence that show a selective inhibition by flumazenil of the up‐regulation of α4‐subunit expression elicited by ethanol withdrawal.