Maler Juan Manuel, Esselmann Hermann, Wiltfang Jens, Kunz Nikolaus, Lewczuk Piotr, Reulbach Udo, Bleich Stefan, Rüther Eckart, Kornhuber Johannes
Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Germany.
Brain Res. 2005 Aug 9;1052(2):156-62. doi: 10.1016/j.brainres.2005.06.017.
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 NR2B were quantified by Western immunoblot analysis. Exposure to ethanol (50 mM) caused an increase in the levels of NR1 (137 +/- 11% of untreated control, P = 0.009), NR2A (128 +/- 14%, P = 0.022) and NR2B (136 +/- 19%, P = 0.012). Coincubation with memantine (10 microM) 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.
本研究考察了非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂美金刚对乙醇诱导的NMDA受体上调的影响。将原代谷氨酸能大鼠海马神经元暴露于乙醇和美金刚中5天。通过蛋白质免疫印迹分析对乙醇敏感的NMDA受体亚基NR1、NR2A和NR2B进行定量。暴露于乙醇（50 mM）导致NR1水平升高（未处理对照的137±11%，P = 0.009）、NR2A水平升高（128±14%，P = 0.022）和NR2B水平升高（136±19%，P = 0.012）。与美金刚（10 μM）共同孵育完全阻断了乙醇诱导的NR1上调（102±4%）、NR2A上调（95±7%）和NR2B上调（105±13%）。除了NR2A出现下降（79±6%，P = 0.034）外，未观察到美金刚对NR亚基表达有影响。在所测试的浓度下，单独或联合使用乙醇和美金刚均无毒性。这些结果可能为美金刚对乙醇戒断综合征中反映的乙醇诱导的谷氨酸能兴奋性过高以及乙醇依赖发展的有益作用提供分子解释。
