The role of the NMDA receptor in ethanol withdrawal.
The function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is very sensitive to acute inhibition by ethanol. Because of the role of this receptor in processes such as synaptic plasticity and neuronal development, it may contribute to the acute cognitive deficits caused by ethanol, or to the deleterious effects of ethanol during gestation. Excessive stimulation of the NMDA receptor is believed to be involved in the generation of epileptiform seizure activity as well as in excitotoxic cell death. Our studies have demonstrated that there is an adaptive "up-regulation" of NMDA receptor function in brains of chronically ethanol-treated animals and in cultured cells that have been exposed chronically to ethanol. This up-regulation appears to contribute to ethanol withdrawal seizure activity, since withdrawal seizures can be attenuated by specific NMDA receptor antagonists, and the time course of the change in receptor number parallels the time course of withdrawal seizures. In addition, cells exposed chronically to ethanol are significantly more susceptible to glutamate-induced cell death, which is mediated by the NMDA receptor, indicating a key role of the NMDA receptor in the well-characterized neuronal damage that is observed after chronic ethanol exposure and withdrawal in animals and humans. Understanding the basis for withdrawal seizures and withdrawal-induced neurotoxicity provides for the development of specific and selective therapeutic agents to ameliorate these consequences of chronic ethanol exposure and withdrawal.
University of Colorado Health Sciences Center, Department of Pharmacology, Denver 80262.
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Hoffman
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Tabakoff
D000818:Animals; D002531:Cerebellum / Q000502:physiology; D000431:Ethanol / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate