GLUTAMATE RECEPTORS IN ALCOHOL WITHDRAWAL-INDUCED NEUROTOXICITY

Chronic ethanol ingestion results in an ''up-regulation'' of the N-met hyl-D-aspartate (NMDA) subtype of glutamate receptor in mouse brain. T his increase in receptors is associated with ethanol withdrawal seizur es, which can be attenuated by NMDA receptor antagonists. Chronic expo sure to ethanol (3 days) of rat cerebellar granule cells in primary cu lture also produces an increase in NMDA receptor number and function, which leads to enhanced susceptibility to glutamate-induced neurotoxic ity. Antagonists acting at various sites on the NMDA receptor can bloc k glutamate excitotoxicity in both control and ethanol-exposed cells. These results suggest the possibility of developing agents that will a meliorate ethanol withdrawal seizures as well as withdrawal-induced ne uronal damage. In addition, acute (2 hr) or chronic (3 day) exposure o f cerebellar granule cells to ganglioside GM(1) protects control and e thanol-treated cells against glutamate neurotoxicity. However, while t he acute GM(1) 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 sugge st that the mechanism by which acute and chronic ganglioside treatment s protect against glutamate neurotoxicity may differ. Furthermore, chr onic ganglioside treatment during ethanol exposure has the potential t o prevent the ethanol-induced up-regulation of NMDA receptors that und erlies withdrawal seizures and increased susceptibility to excitotoxic ity.