RT Journal Article SR Electronic T1 Changes in GABAA Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 11711 OP 11724 DO 10.1523/JNEUROSCI.23-37-11711.2003 VO 23 IS 37 A1 Enrico Sanna A1 Maria Cristina Mostallino A1 Fabio Busonero A1 Giuseppe Talani A1 Stefania Tranquilli A1 Manuel Mameli A1 Saturnino Spiga A1 Paolo Follesa A1 Giovanni Biggio YR 2003 UL http://www.jneurosci.org/content/23/37/11711.abstract AB Changes in the expression of subunits of the GABA type A (GABAA) receptor are implicated in the development of ethanol tolerance and dependence as well as in the central hyperexcitability associated with ethanol withdrawal. The impact of such changes on GABAA receptor function and pharmacological sensitivity was investigated with cultured rat hippocampal neurons exposed to ethanol for 5 d and then subjected to ethanol withdrawal. Both ethanol treatment and withdrawal were associated with a marked decrease in the maximal density of GABA-evoked Cl- currents, whereas the potency of GABA was unaffected. Ethanol exposure also reduced the modulatory efficacy of the benzodiazepine receptor agonists lorazepam, zolpidem, and zaleplon as well as that of the inverse agonists Ro 15-4513 and FG 7142, effects that were associated with a reduced abundance of mRNAs encoding the receptor subunits α1, α3, γ2L, and γ2S. Ethanol withdrawal restored the efficacy of lorazepam, but not that of low concentrations of zolpidem or zaleplon, to control values. Flumazenil, which was ineffective in control neurons, and Ro 15-4513 each potentiated the GABA response after ethanol withdrawal. These effects of withdrawal were accompanied by upregulation of the α2, α3, and α4 subunit mRNAs as well as of the α4 protein. Diazepam or γ-hydroxybutyrate, but not baclofen, prevented the changes in both GABAA receptor pharmacology and subunit mRNA levels induced by ethanol withdrawal. Changes in GABAA receptor gene expression induced by prolonged exposure to and withdrawal of ethanol are thus associated with altered GABAA receptor function and pharmacological sensitivity.