Gamma-aminobutyric acid type A receptors and alcoholism: intoxication, dependence, vulnerability, and treatment.
BACKGROUND
Alcohol facilitates gamma-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.


METHODS
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.
Krystal
John H
JH
Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, 950 Campbell Avenue, New Haven, CT 06516, USA. john.krystal@yale.edu
Staley
Julie
J
Mason
Graeme
G
Petrakis
Ismene L
IL
Kaufman
Joan
J
Harris
R Adron
RA
Gelernter
Joel
J
Lappalainen
Jaakko
J
D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid