Glutamate-induced increase of extracellular glutamate through N-methyl-D-aspartate receptors in ethanol withdrawal

Ethanol withdrawal is a physiopathological state associated with increased number and function of N-methyl-D-aspartate glutamate receptors. We assesse d the effect of N-methyl-D-aspartate receptor stimulation on the extracellu lar levels of glutamate in vivo by the focal application of N-methyl-D-aspa rtate in the striatum of dependent rats following withdrawal from chronic t reatment with ethanol. In control, chronic sucrose-treated rats, 800 mu M N -methyl-D-aspartate increased glutamate levels to 268% of baseline values. In ethanol-withdrawn animals, 12 h after interruption of the chronic treatm ent, the application of N-methyl-D-aspartate increased glutamate levels to 598% of baseline values. In ethanol-intoxicated rats N-methyl-D-aspartate w as ineffective. Concentration-response curves showed that in ethanol withdr awn animals N-methyl-D-aspartate was five-fold more potent than in controls . In withdrawn animals, the non-competitive N-methyl-D-aspartate receptor a ntagonist dizocilpine (1.0 mg/kg i.p.) or ethanol (5 g/kg i.g.) markedly re duced the N-methyl-D-aspartate-induced increase in glutamate levels. These results are consistent with the up-regulation of N-methyl-D-aspartate receptors by chronic ethanol and add biochemical evidence for the presence of N-methyl-D-aspartate receptors facilitating glutamate release through a positive feedback mechanism. The glutamate-induced, N-methyl-D-aspartate r eceptor-mediated elevations of extracellular glutamate may constitute a neu rochemical substrate for the neuropathological alterations associated with alcoholism. (C) 1999 IBRO. Published by Elsevier Science Ltd.