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Am J Psychiatry 1995; 152:332-340
Copyright © 1995 by American Psychiatric Association
The glutamatergic basis of human alcoholism
G Tsai, DR Gastfriend and JT Coyle
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital.
OBJECTIVE: Although alcoholism is one of the most common psychiatric
diagnoses, understanding of its pathophysiology remains poor. Accumulating
evidence suggests that neurophysiological and pathological effects of
ethanol are mediated to a considerable extent through the glutamatergic
system. This article reviews the evidence of ethanol's effects on
glutamatergic transmission and proposes a glutamatergic basis for
alcoholism. METHOD: The information was derived from original research. The
authors located more than 100 articles from psychiatry and neuroscience
journals that related ethanol to glutamatergic transmission. They
critically reviewed the neurobiology of the glutamatergic system in
alcoholism and synthesized a unifying glutamatergic theory. RESULTS: Acute
effects of ethanol disrupt glutamatergic neurotransmission by inhibiting
the response of the N- methyl-D-aspartate (NMDA) receptor. Prolonged
inhibition of the NMDA receptor by ethanol results in development of
supersensitivity; acute removal of ethanol causes marked augmentation of
activity of postsynaptic neurons, such as those in the noradrenergic
system, and, in the extreme, glutamate-induced excitotoxicity.
Neurobiological effects of alcoholism, such as intoxication, withdrawal
seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol
syndrome, can be understood as a spectrum of consequences of ethanol's
effect on the glutamatergic system. CONCLUSIONS: A host of findings support
the hypothesis that the unifying mechanism of action of ethanol in
interference with glutamatergic neurotransmission, especially through the
NMDA receptor. Alcoholism may be considered another member of the expanding
family of glutamate-related neuropsychiatric disorders. These insights
should increase understanding of the biologic vulnerabilities leading to
ethanol abuse and dependence and aid development of more effective
pharmacologic interventions.
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