RT Journal Article SR Electronic T1 γ-Hydroxybutyric Acid and Diazepam Antagonize a Rapid Increase in GABAA Receptors α4 Subunit mRNA Abundance Induced by Ethanol Withdrawal in Cerebellar Granule Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 896 OP 907 DO 10.1124/mol.63.4.896 VO 63 IS 4 A1 Paolo Follesa A1 Luisa Mancuso A1 Francesca Biggio A1 Maria Cristina Mostallino A1 Annalisa Manca A1 Maria Paola Mascia A1 Fabio Busonero A1 Giuseppe Talani A1 Enrico Sanna A1 Giovanni Biggio YR 2003 UL http://molpharm.aspetjournals.org/content/63/4/896.abstract AB Both benzodiazepines and γ-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrome. The molecular basis for this therapeutic efficacy was investigated with primary cultures of rat cerebellar granule cells. Long-term exposure of these cells to ethanol (100 mM, 5 days) reduced the abundance of mRNAs encoding the γ2L and γ2S subunits of the GABA type A receptor (−32 and −23%, respectively) but failed to affect that of α1, α4, or α6 subunit mRNAs. Subsequent ethanol withdrawal resulted in decreases in the amounts of α1 (−29%), α6 (−27%), γ2L (−64%), and γ2S (−76%),subunit mRNAs that were maximal after 6 to 12 h. In contrast, 3 h after ethanol withdrawal, the abundance of the α4 subunit mRNA was increased by 46%. Ethanol withdrawal did not affect neuronal morphology but reduced cellular metabolic activity. The increase in α4 subunit was confirmed by functional studies showing a positive action of flumazenil in patch clamp recordings of GABA-stimulated currents after ethanol withdrawal. Diazepam (10 μM) or GHB (100 mM) prevented the increase in the amount of the α4 subunit mRNA, the metabolic impairment, and the positive action of flumazenil induced by ethanol withdrawal but failed to restore the expression of the α1 and γ2subunits. The antagonism by GHB seems not to be mediated by a direct action at GABAAR because GHB failed to potentiate the effects of GABA or diazepam on Cl− currents mediated by GABA type A receptor. The American Society for Pharmacology and Experimental Therapeutics