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