The glutamatergic basis of human alcoholism.
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.


METHODS
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.
Tsai
G
G
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital.
Gastfriend
D R
DR
Coyle
J T
JT
D000428:Alcohol Drinking / Q000009:adverse effects; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005971:Glutamates / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D011604:Psychoses, Alcoholic / Q000503:physiopathology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D005971:Glutamates; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol