PT  - JOURNAL ARTICLE
AU  - Enrico Sanna
AU  - Maria Cristina Mostallino
AU  - Fabio Busonero
AU  - Giuseppe Talani
AU  - Stefania Tranquilli
AU  - Manuel Mameli
AU  - Saturnino Spiga
AU  - Paolo Follesa
AU  - Giovanni Biggio
TI  - Changes in GABA<sub>A</sub> Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal
AID  - 10.1523/JNEUROSCI.23-37-11711.2003
DP  - 2003 Dec 17
TA  - The Journal of Neuroscience
PG  - 11711--11724
VI  - 23
IP  - 37
4099  - http://www.jneurosci.org/content/23/37/11711.short
4100  - http://www.jneurosci.org/content/23/37/11711.full
SO  - J. Neurosci.2003 Dec 17; 23
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.