Glutamate receptors in alcohol withdrawal-induced neurotoxicity.
Chronic ethanol ingestion results in an "up-regulation" of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in mouse brain. This increase in receptors is associated with ethanol withdrawal seizures, which can be attenuated by NMDA receptor antagonists. Chronic exposure to ethanol (3 days) of rat cerebellar granule cells in primary culture also produces an increase in NMDA receptor number and function, which leads to enhanced susceptibility to glutamate-induced neurotoxicity. Antagonists acting at various sites on the NMDA receptor can block glutamate excitotoxicity in both control and ethanol-exposed cells. These results suggest the possibility of developing agents that will ameliorate ethanol withdrawal seizures as well as withdrawal-induced neuronal damage. In addition, acute (2 hr) or chronic (3 day) exposure of cerebellar granule cells to ganglioside GM1 protects control and ethanol-treated cells against glutamate neurotoxicity. However, while the acute GM1 treatment does not interfere with the initial response to glutamate (increase in intracellular Ca2+), this response is "down-regulated" after chronic ganglioside treatment. These findings suggest that the mechanism by which acute and chronic ganglioside treatments protect against glutamate neurotoxicity may differ. Furthermore, chronic ganglioside treatment during ethanol exposure has the potential to prevent the ethanol-induced up-regulation of NMDA receptors that underlies withdrawal seizures and increased susceptibility to excitotoxicity.
Hoffman
P L
PL
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
D000437:Alcoholism / Q000150:complications*; D000818:Animals; D001925:Brain Damage, Chronic / Q000139:chemically induced; D002118:Calcium; D002470:Cell Survival; D002531:Cerebellum / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013375:Substance Withdrawal Syndrome / Q000209:etiology*
D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D002118:Calcium