Mernantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons

The present study examined the effect of memantine, an uncompetitive NMDA receptor antagonist, on ethanol-induced NMDA receptor up-regulation. Primary glutamatergic rat hippocampal neurons were exposed to ethanol and memantine for 5 days. The ethanol-sensitive NMDA receptor subunits NR1, NR2A and NR213 were quantified by Western immunoblot analysis. Fxposure to ethanol (50 mM) caused an increase in the levels of NRI (137 +/- 11 % of untreated control, P = 0.009), NR2A (128 +/- 14 %. P 0.022) and N213 (136 +/- 119 %, P = 0.012). Coincubation with memantine (10 mu M) completely blocked the ethanol-induced up-regulation of NR1 (102, 4 %) NR2A (95 +/- 7 %) and NR2B (105 +/- 13 %). No effect of memantine on NR subunit expression was observable, except for NR2A, where a decrease (79 +/- 6 %, P = 0.034) was noted. Neither ethanol nor memantine alone or in combination were toxic in the concentrations tested. These results may provide a molecular explanation for beneficial effects of memantine on ethanol-induced glutamatergic hyperexcitability reflected in the ethanol withdrawal syndrome and on the development of ethanol dependence. (c) 2005 Elsevier B.V. All rights reserved.