Changes in GABA(A) receptor gene expression associated with selective alterations in receptor function and pharmacology after ethanol withdrawal.

Details

Serval ID
serval:BIB_7218CB08CBED
Type
Article: article from journal or magazin.
Collection
Publications
Title
Changes in GABA(A) receptor gene expression associated with selective alterations in receptor function and pharmacology after ethanol withdrawal.
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Author(s)
Sanna E., Mostallino M.C., Busonero F., Talani G., Tranquilli S., Mameli M., Spiga S., Follesa P., Biggio G.
ISSN
1529-2401 (Electronic)
ISSN-L
0270-6474
Publication state
Published
Issued date
17/12/2003
Peer-reviewed
Oui
Volume
23
Number
37
Pages
11711-11724
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Changes in the expression of subunits of the GABA type A (GABA(A)) 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 GABA(A) 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 alpha1, alpha3, gamma2L, and gamma2S. 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 alpha2, alpha3, and alpha4 subunit mRNAs as well as of the alpha4 protein. Diazepam or gamma-hydroxybutyrate, but not baclofen, prevented the changes in both GABA(A) receptor pharmacology and subunit mRNA levels induced by ethanol withdrawal. Changes in GABA(A) receptor gene expression induced by prolonged exposure to and withdrawal of ethanol are thus associated with altered GABA(A) receptor function and pharmacological sensitivity.

Keywords
Animals, Baclofen/pharmacology, Cells, Cultured, Chloride Channels/metabolism, Diazepam/pharmacology, Electric Conductivity, Ethanol/pharmacology, GABA-A Receptor Agonists, Gene Expression Regulation, Hippocampus/cytology, Hippocampus/metabolism, Hippocampus/physiology, Neurons/cytology, Neurons/metabolism, Neurons/physiology, Patch-Clamp Techniques, RNA, Messenger/metabolism, Rats, Rats, Sprague-Dawley, Receptors, GABA-A/genetics, Receptors, GABA-A/metabolism, Receptors, GABA-A/physiology, Sodium Oxybate/pharmacology
Pubmed
Create date
03/02/2017 11:32
Last modification date
20/08/2019 14:30
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