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GABA Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment (2006)

GABA Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment (2006)

  1. Jatelka
    Arch Gen Psychiatry. 2006;63:957-968

    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

    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

    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 benzodiazepineinsensitive 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 longterm 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