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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 GABAA 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 GABAA receptor (GABAAR) responsiveness and a gain of synaptic GABAAR 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 GABAAR 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 GABAAR sensitivity to low [EtOH]. The profound alterations in EtOH sensitivity and 4 subunit localization at hippocampal GABAARs 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, GABAA receptor
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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