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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 (GABA_A) 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 GABA_A receptor subclass that shows high affinity for GABA and neurosteroids, relative insensitivity to benzodiazepines, low chloride conductance, and an extrasynaptic location. Variation in GABA_A 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 GABA_A receptor density and subunit gene expression levels that contribute to a withdrawal-related deficit in GABA_A 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 GABA_A 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, GABA_A 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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