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首页> 外文期刊>Current drug targets. CNS and neurological disorders >The NR2B Subtype of NMDA Receptor: A Potential Target for the Treatment of Alcohol Dependence.
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The NR2B Subtype of NMDA Receptor: A Potential Target for the Treatment of Alcohol Dependence.

机译：NMDA受体的NR2B亚型：酒精依赖治疗的潜在目标。

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Ethanol is a small molecule acting on several neurotransmitter systems in the brain. Accumulating evidences suggest that the primary excitatory - i.e. the glutamatergic - neurotransmitter system is a particularly important site of ethanol's action. Several studies showed that ethanol is a potent and selective inhibitor of the N-methyl-D-aspartate (NMDA) receptors and prolonged ethanol exposition leads to a compensatory up-regulation receptor-mediated functions after removal of ethanol. These alterations are supposed to contribute to the development of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal. In recent papers, alterations in subunit composition of NMDA receptors were reported after long term ethanol exposure. mRNA and/or protein levels of NR2A and NR2B types of subunits were found elevated both by in vivo and in vitro experiments. Our results showed that especially the NR2B subunit expression is increased in cultured hippocampal and cortical neurones after 3 days of intermittent ethanol treatment. According to the high calcium permeability, the increased agonist sensitivity and the relatively slow closing kinetics of NMDA ion channels composed of NR2B subunits, the above mentioned changes may underlie the enhanced NMDA receptor activation observed after long term ethanol exposure. Accordingly, we have tested NR2B subunit selective NMDA receptor antagonists in primary cultures of rat cortical neurones pre-treated with ethanol intermittently for 3 days and found that these compounds potently inhibited the neurotoxic effect of ethanol withdrawal. Hypothesising the involvement of enhanced NR2B subunit expression in development of alcohol dependence and withdrawal symptoms and considering the tolerable side effect profile of the NR2B subunit selective NMDA receptor antagonists, the NR2B type of NMDA receptor subunit may serve as a possible drug target in pharmacological interventions for alcoholism. The aim of this review is to give an update on the role of altered structure and function of NMDA receptors after ethanol exposure and to summarise the recent data about the activity of NR2B subunit selective NMDA receptor antagonists in model systems related to alcoholism.
机译：乙醇是一种小分子，可作用于大脑中的多个神经递质系统。越来越多的证据表明，主要的兴奋性即谷氨酸能神经递质系统是乙醇作用的一个特别重要的部位。几项研究表明，乙醇是N-甲基-D-天冬氨酸（NMDA）受体的有效和选择性抑制剂，长时间的乙醇暴露会在去除乙醇后导致补偿性上调受体介导的功能。这些改变被认为有助于乙醇耐受性，依赖性以及乙醇戒断的急性和延迟症状的发展。在最近的论文中，长期乙醇暴露后，NMDA受体亚基组成发生了变化。通过体内和体外实验发现NR2A和NR2B类型的亚基的mRNA和/或蛋白质水平升高。我们的研究结果表明，间歇性乙醇处理3天后，尤其是在培养的海马和皮层神经元中NR2B亚基表达增加。由于高钙渗透性，增加的激动剂敏感性和由NR2B亚基组成的NMDA离子通道相对较慢的闭合动力学，上述变化可能是长期乙醇暴露后观察到的NMDA受体活化增强的基础。因此，我们在用乙醇预处理3天的大鼠皮质神经元的原代培养物中测试了NR2B亚基选择性NMDA受体拮抗剂，发现这些化合物有效抑制了乙醇戒断的神经毒性作用。假设增强的NR2B亚基表达参与酒精依赖和戒断症状的发展，并考虑到NR2B亚基选择性NMDA受体拮抗剂的可耐受副作用，则NMDA受体亚基的NR2B类型可能作为药物干预中的靶标酗酒。这篇综述的目的是提供关于乙醇暴露后NMDA受体改变的结构和功能的作用的最新进展，并总结关于NR2B亚基选择性NMDA受体拮抗剂在与酒精中毒有关的模型系统中活性的最新数据。

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