Ma Yao-Ying, Guo Chang-Yong, Yu Peng, Lee David Yue-Wei, Han Ji-Sheng, Cui Cai-Lian
Neuroscience Research Institute and Department of Neurobiology, Peking University Health Science Center, Key Laboratory of Neuroscience, The Ministry of Education and Ministry of Public Health, 38 Xueyuan Road, Beijing 100083, PR China.
Exp Neurol. 2006 Aug;200(2):343-55. doi: 10.1016/j.expneurol.2006.02.117. Epub 2006 Apr 24.
It has been reported that N-methyl-D-aspartate (NMDA) receptor is implicated in drug addiction and antagonists of the NMDA receptor complex can inhibit the development and expression of conditioned place preference (CPP) induced by several addictive drugs, implying that this class of compounds might be considered as candidate for the treatment of substance abuse. To explore this possibility, it is important to evaluate whether the inhibitory effect of NMDA receptor antagonists would be confined to behaviors produced by drugs of abuse only, but not by natural reinforcers. According to the quantitative changes of NMDA receptor subunits, including NR1, NR2A, and NR2B, induced by diverse types of reinforcers, we chose NR2B subunit as the target of research. Experimental results showed that (1) an augmented expression of NR2B subunit was revealed by Western blotting in the nucleus accumbens (NAc) and the hippocampus in rats with CPP induced by morphine, but not by natural rewards such as food, novel environment and social interaction. (2) Ifenprodil, an antagonist highly selective for NR2B subunit of the NMDA receptor, produced a dose-dependent reduction in CPP induced by morphine and novel environment, but not that by food consumption and social interaction. Taking together, these findings suggested that NR2B containing NMDA receptor may be more involved with morphine reward rather than natural rewards, and that antagonism of NR2B may have a potential for the treatment of morphine abuse.
据报道，N-甲基-D-天冬氨酸（NMDA）受体与药物成瘾有关，NMDA受体复合物的拮抗剂可抑制多种成瘾药物诱导的条件性位置偏爱（CPP）的形成和表达，这意味着这类化合物可能被视为治疗药物滥用的候选药物。为了探究这种可能性，评估NMDA受体拮抗剂的抑制作用是否仅局限于滥用药物产生的行为，而不是自然强化物产生的行为，这一点很重要。根据不同类型强化物诱导的NMDA受体亚基（包括NR1、NR2A和NR2B）的定量变化，我们选择NR2B亚基作为研究靶点。实验结果表明：（1）通过蛋白质免疫印迹法发现，吗啡诱导产生CPP的大鼠伏隔核（NAc）和海马中NR2B亚基的表达增加，而食物、新环境和社交互动等自然奖赏不会导致这种增加。（2）ifenprodil是一种对NMDA受体NR2B亚基具有高度选择性的拮抗剂，它能剂量依赖性地降低吗啡和新环境诱导的CPP，但对食物摄取和社交互动诱导的CPP没有影响。综上所述，这些发现表明，含NR2B的NMDA受体可能更多地参与吗啡奖赏而非自然奖赏，并且拮抗NR2B可能具有治疗吗啡滥用的潜力。
