Type A gamma-aminobutyric acid receptors and alcoholism: intoxication, dependence, susceptibility, and treatment

Alcohol facilitates gamma-aminobutyric acid (GABA) function, and GABA type A (GABA(A)) receptor-promoting agents suppress alcohol withdrawal symptoms. Advances in molecular neuroscience, genetics, and neuroimaging are providing new insights into the role of brain GABA systems in short- and long-term alcohol effects.

Alcohol increases GABA release, increases neurosteroid levels, and can greatly enhance the function of a subclass of GABA(A) receptors that has high affinity for GABA and neurosteroids, relative insensitivity to benzodiazepines, low chloride conductance, and extrasynaptic localization. Variations in GABA(A) receptor subunit genes may contribute to susceptibility to alcoholism, particularly in the context of environmental risk factors.

Alcohol dependence is associated with time-dependent changes in GABA(A) receptor density and subunit gene expression levels in the brain, which contribute to an inflammation-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, new treatments target the tonic component of GABA neurotransmission mediated by benzodiazepine-insensitive GABA(A) receptors.

Smoking attenuates inflammation-related perturbations of GABA function in the brain and may contribute to comorbid nicotine and alcohol dependence. GABA systems show recovery with long-term sobriety.

Recent research deepens our understanding of the role of GABA systems in alcohol effects, alcohol dependence, and susceptibility to alcoholism. GABA(A) receptor subtype-selective treatments also merit investigation for reducing withdrawal symptoms and alcohol consumption in alcohol-dependent individuals.

Arch Gen Psychiatry.: Gamma-aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment

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