QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, December 17, 2003, 23(37):11711-11724

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (47) Citing Articles via Google Scholar Google Scholar Articles by Sanna, E. Articles by Biggio, G. Search for Related Content PubMed PubMed Citation Articles by Sanna, E. Articles by Biggio, G.

 Previous Article  |  Next Article 

Cellular/Molecular
Changes in GABA_A Receptor Gene Expression Associated with Selective Alterations in Receptor Function and Pharmacology after Ethanol Withdrawal

Enrico Sanna,^1,2 Maria Cristina Mostallino,^1,2,4 Fabio Busonero,^1,2 Giuseppe Talani,^1,2 Stefania Tranquilli,^1,2 Manuel Mameli,^1,2 Saturnino Spiga,³ Paolo Follesa,^1,2 and Giovanni Biggio^1,2,4

¹Department of Experimental Biology, Section of Neuroscience, ²Center of Excellence for the "Neurobiology of Dependence," and ³Department of Animal Biology and Ecology, University of Cagliari, 09123 Cagliari, Italy, and ⁴Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 09123 Cagliari, Italy

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 1, 3, 2L, and 2S. 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 2, 3, and 4 subunit mRNAs as well as of the 4 protein. Diazepam or -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.

Key words: GABA_A receptor; ethanol; tolerance; dependence; gene expression; hippocampal neurons; patch clamp; -hydroxybutyrate; diazepam

---

Received July 1, 2003; revised October 16, 2003; accepted October 17, 2003.

This article has been cited by other articles:

				E. Sanna, M. C. Mostallino, L. Murru, M. Carta, G. Talani, S. Zucca, M. L. Mura, E. Maciocco, and G. Biggio Changes in Expression and Function of Extrasynaptic GABAA Receptors in the Rat Hippocampus during Pregnancy and after Delivery J. Neurosci., February 11, 2009; 29(6): 1755 - 1765. [Abstract] [Full Text] [PDF]

				A McKeon, M A Frye, and N. Delanty The alcohol withdrawal syndrome J. Neurol. Neurosurg. Psychiatry, August 1, 2008; 79(8): 854 - 862. [Abstract] [Full Text] [PDF]

				L. Pignataro, A. N. Miller, L. Ma, S. Midha, P. Protiva, D. G. Herrera, and N. L. Harrison Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1 J. Neurosci., November 21, 2007; 27(47): 12957 - 12966. [Abstract] [Full Text] [PDF]

				H. C. Urschel III, L. L. Hanselka, I. Gromov, L. White, and M. Baron Open-Label Study of a Proprietary Treatment Program Targeting Type A {gamma}-Aminobutyric Acid Receptor Dysregulation in Methamphetamine Dependence Mayo Clin. Proc., October 1, 2007; 82(10): 1170 - 1178. [Abstract] [Full Text] [PDF]

				J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen {gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment. Arch Gen Psychiatry, September 1, 2006; 63(9): 957 - 968. [Abstract] [Full Text] [PDF]

				J. K. Staley, C. Gottschalk, I. L. Petrakis, R. Gueorguieva, S. O'Malley, R. Baldwin, P. Jatlow, N. P. L. G. Verhoeff, E. Perry, D. Weinzimmer, et al. Cortical {gamma}-Aminobutyric Acid Type A-Benzodiazepine Receptors in Recovery From Alcohol Dependence: Relationship to Features of Alcohol Dependence and Cigarette Smoking Arch Gen Psychiatry, August 1, 2005; 62(8): 877 - 888. [Abstract] [Full Text] [PDF]

				L. Ma, L. Song, G. E. Radoi, and N. L. Harrison Transcriptional Regulation of the Mouse Gene Encoding the {alpha}-4 Subunit of the GABAA Receptor J. Biol. Chem., September 24, 2004; 279(39): 40451 - 40461. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help