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The Journal of Neuroscience, February 8, 2006, 26(6):1749-1758; doi:10.1523/JNEUROSCI.4702-05.2006

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Neurobiology of Disease
Chronic Intermittent Ethanol-Induced Switch of Ethanol Actions from Extrasynaptic to Synaptic Hippocampal GABA_A Receptors

Jing Liang,^1,2 Nianhui Zhang,³ Elisabetta Cagetti,² Carolyn R. Houser,³ Richard W. Olsen,² and Igor Spigelman¹

¹Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, and Departments of ²Molecular and Medical Pharmacology and ³Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Dr. Igor Spigelman, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 63-078 (Center for Health Sciences), Los Angeles, CA 90095-1668. Email: igor{at}ucla.edu

Alcohol withdrawal syndrome (AWS) symptoms include hyperexcitability, anxiety, and sleep disorders. Chronic intermittent ethanol (CIE) treatment of rats with subsequent withdrawal of ethanol (EtOH) reproduced AWS symptoms in behavioral assays, which included tolerance to the sleep-inducing effect of acute EtOH and its maintained anxiolytic effect. Electrophysiological assays demonstrated a CIE-induced long-term loss of extrasynaptic GABA_A receptor (GABA_AR) responsiveness and a gain of synaptic GABA_AR responsiveness of CA1 pyramidal and dentate granule neurons to EtOH that we were able to relate to behavioral effects. After CIE treatment, the 4 subunit-preferring GABA_AR ligands 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, La³⁺, and Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5][1,4]benzodiazepine-3-carboxylate) exerted decreased effects on extrasynaptic currents but had increased effects on synaptic currents. Electron microscopy revealed an increase in central synaptic localization of 4 but not subunits within GABAergic synapses on the dentate granule cells of CIE rats. Recordings in dentate granule cells from subunit-deficient mice revealed that this subunit is not required for synaptic GABA_AR sensitivity to low [EtOH]. The profound alterations in EtOH sensitivity and 4 subunit localization at hippocampal GABA_ARs of CIE rats suggest that such changes in these and other relevant brain circuits may contribute to the development of tolerance to the sleep-inducing effects and long-term dependence on alcohol.

Key words: subunit composition; anxiety; sleep; electron microscopy; alcoholism; inhibitory neurotransmission, GABA_A receptor

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Received Nov. 2, 2005; revised Dec. 21, 2005; accepted Dec. 26, 2005.

Correspondence should be addressed to Dr. Igor Spigelman, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Avenue, 63-078 (Center for Health Sciences), Los Angeles, CA 90095-1668. Email: igor{at}ucla.edu

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