γ-Aminobutyric acid type A receptors and alcoholism: Intoxication, dependence, vulnerability, and treatment

Context: Alcohol facilitates γ-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.