Flumazenil selectively prevents the increase in alpha(4)-subunit gene expression and an associated change in GABA(A) receptor function induced by ethanol withdrawal

• Published in: Journal of neurochemistry Vol. 102; no. 3; p. 657
• Main Authors: Biggio, Francesca, Gorini, Giorgio, Caria, Stefania, Murru, Luca, Sanna, Enrico, Follesa, Paolo
• Format: Journal Article
• Language: English
• Published: England 01.08.2007
• Subjects: Acetamides - pharmacology; Alcohol-Induced Disorders, Nervous System - drug therapy; Alcohol-Induced Disorders, Nervous System - genetics; Alcohol-Induced Disorders, Nervous System - metabolism; Animals; Animals, Newborn; Anticonvulsants - pharmacology; Cells, Cultured; Central Nervous System Depressants - adverse effects; Drug Interactions - physiology; Drug Tolerance - physiology; Ethanol - adverse effects; Flumazenil - pharmacology; GABA Modulators - pharmacology; gamma-Aminobutyric Acid - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Patch-Clamp Techniques; Protein Subunits - genetics; Protein Subunits - metabolism; Pyrimidines - pharmacology; Rats; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - genetics; Substance Withdrawal Syndrome - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 0022-3042
• DOI: 10.1111/j.1471-4159.2007.04512.x

The actions of ethanol on gamma-aminobutyric acid type A (GABA(A)) 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 GABA(A) 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 GABA(A) receptors. In the present work, we investigated the effects, on such changes, of the benzodiazepine receptor antagonist flumazenil that can positively modulate alpha(4)-containing receptors. We here report that flumazenil prevented both the ethanol withdrawal-induced up-regulation of the alpha(4)-subunit and the increase in its own modulatory action. In contrast, flumazenil did not inhibit ethanol withdrawal-induced decrease in alpha(1)- and delta-subunit expression as well as the corresponding decrease in the modulatory action on GABA(A) receptor function of both the alpha(1)-selective ligand zaleplon and the delta-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 alpha(4)-subunit expression elicited by ethanol withdrawal.