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The Journal of Neuroscience, November 7, 2007, 27(45):12367-12377; doi:10.1523/JNEUROSCI.2786-07.2007

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Neurobiology of Disease
Mechanisms of Reversible GABA_A Receptor Plasticity after Ethanol Intoxication

Jing Liang,^1,2 * Asha Suryanarayanan,^2 * Alana Abriam,¹ Bradley Snyder,¹ Richard W. Olsen,² and Igor Spigelman¹

¹Division of Oral Biology and Medicine, School of Dentistry, and ²Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to either of the following: Dr. Igor Spigelman, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, 10833 LeConte Avenue, 63-078 CHS, Los Angeles, CA 90095-1668, Email: igor{at}ucla.edu; or Dr. Richard W. Olsen, Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, Email: rolsen{at}mednet.ucla.edu

The time-dependent effects of ethanol (EtOH) intoxication on GABA_A receptor (GABA_AR) composition and function were studied in rats. A cross-linking assay and Western blot analysis of microdissected CA1 area of hippocampal slices obtained 1 h after EtOH intoxication (5 g/kg, gavage), revealed decreases in the cell-surface fraction of 4 and , but not 1, 5, or 2 GABA_AR subunits, without changes in their total content. This was accompanied (in CA1 neuron recordings) by decreased magnitude of the picrotoxin-sensitive tonic current (I_tonic), but not miniature IPSCs (mIPSCs), and by reduced enhancement of I_tonic by EtOH, but not by diazepam. By 48 h after EtOH dosing, cell-surface 4 (80%) and 2 (82%) subunit content increased, and cell-surface 1 (–50%) and (–79%) and overall content were decreased. This was paralleled by faster decay of mIPSCs, decreased diazepam enhancement of both mIPSCs and I_tonic, and paradoxically increased mIPSC responsiveness to EtOH (10–100 mM). Sensitivity to isoflurane- or diazepam-induced loss of righting reflex was decreased at 12 and 24 h after EtOH intoxication, respectively, suggesting functional GABA_AR tolerance. The plastic GABA_AR changes were gradually and fully reversible by 2 weeks after single EtOH dosing, but unexplainably persisted long after withdrawal from chronic intermittent ethanol treatment, which leads to signs of alcohol dependence. Our data suggest that early tolerance to EtOH may result from excessive activation and subsequent internalization of 4ß extrasynaptic GABA_ARs. This leads to transcriptionally regulated increases in 4 and 2 and decreases in 1 subunits, with preferential insertion of the newly formed 4ß2 GABA_ARs at synapses.

Key words: alcoholism; inhibitory neurotransmission; subunit composition; GABA receptor; tolerance; dependence

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Received June 19, 2007; revised Sept. 18, 2007; accepted Sept. 19, 2007.

Correspondence should be addressed to either of the following: Dr. Igor Spigelman, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, 10833 LeConte Avenue, 63-078 CHS, Los Angeles, CA 90095-1668, Email: igor{at}ucla.edu; or Dr. Richard W. Olsen, Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, Email: rolsen{at}mednet.ucla.edu

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