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 -Aminobutyric Acid Type A Receptors and Alcoholism
Intoxication, Dependence, Vulnerability, and Treatment
John H. Krystal, MD;
Julie Staley, PhD;
Graeme Mason, PhD;
Ismene L. Petrakis, MD;
Joan Kaufman, PhD;
R. Adron Harris, PhD;
Joel Gelernter, MD;
Jaakko Lappalainen, MD, PhD
Arch Gen Psychiatry. 2006;63:957-968.
Context Alcohol facilitates  -aminobutyric acid (GABA) function, and GABA type A (GABAA) receptor–facilitating agents suppress alcohol withdrawal symptoms. Advances in molecular neuroscience, genetics, and neuroimaging provide new insights into the role of brain GABA systems in short- and long-term alcohol effects.
Objective To review the role of brain GABA systems in alcohol response, alcohol dependence, alcoholism vulnerability, and alcoholism pharmacotherapy.
Design Literature review.
Results Alcohol increases GABA release, raises neurosteroid levels, and may potently enhance the function of a GABAA receptor subclass that shows high affinity for GABA and neurosteroids, relative insensitivity to benzodiazepines, low chloride conductance, and an extrasynaptic location. Variation in GABAA receptor subunit genes may contribute to the vulnerability to alcoholism, particularly in the context of environmental risk factors. Alcohol dependence is associated with time-dependent changes in brain GABAA receptor density and subunit gene expression levels that contribute to a withdrawal-related deficit in GABAA receptor function. However, cortical GABA levels are not reduced during acute withdrawal. Benzodiazepine-assisted detoxification enhances a phasic component of GABA function. However, novel treatments target the tonic component of GABA neurotransmission mediated by benzodiazepine-insensitive GABAA receptors. Smoking attenuates withdrawal-related disturbances in brain GABA function, perhaps contributing to comorbid nicotine and alcohol dependence. The GABA systems show recovery with long-term sobriety.
Conclusions Recent research deepens our understanding of the role of GABA systems in alcohol action, alcohol dependence, and the vulnerability to alcoholism. Also, GABAA receptor subtype–selective treatments merit exploration for reducing withdrawal symptoms and drinking in alcohol-dependent individuals.
Author Affiliations: Department of Psychiatry (Drs Krystal, Staley, Mason, Petrakis, Kaufman, Gelernter, and Lappalainen), Department of Diagnostic Radiology, the Anlyan Center (Dr Mason), and Division of Human Genetics, Department of Psychiatry (Drs Gelernter and Lappalainen), Yale University School of Medicine, New Haven, Conn; Alcohol Research Center (Drs Krystal, Petrakis, Gelernter, and Lappalainen) and Clinical Neuroscience Division, VA National Center for Post-traumatic Stress Disorder (Drs Krystal, Staley, Petrakis, and Kaufman), VA Connecticut Healthcare System, West Haven; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven (Drs Krystal and Staley); Child Study Center, New Haven (Dr Kaufman); Child and Adolescent Research and Education Program, New Haven (Dr Kaufman); and Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin (Dr Harris). Dr Lappalainen is currently at AstraZeneca Research & Development, Wilmington, Del.
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