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Basic research for the treatment of psychological dependence on methamphetamine

冰毒心理依赖治疗基础研究

基本信息

批准号：
15390085
负责人：
SUZUKI Tsutomu
金额：
$ 3.46万
依托单位：
Hoshi University School of Pharmacy and Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Repeated treatment with methamphetamine leads to an enhancement in the methamphetamine-induced dopamine release and its related behaviors. This phenomenon is called sensitization or reverse tolerance. In this study, I demonstrated the effect of N-methyl-D-aspartate(NMDA) receptor antagonist ifenprodil and κ-opioid receptor agonist TRK-820 on the development of sensitization to the methamphetamine-induced rewarding effect and dopamine release in rodents. The conditioned place preference paradigm and in vivo microdialysis assay were performed in the present study. The treatment with ifenprodil or TRK-820 abolished the enhancement of the methamphetamine-induced place preference following repeated treatment with methamphetamine. Furthermore, intra-nucleus accumbens (N.Acc.) injection of TRK-820 blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. These findings strongly indicate that treatment with ifenprodil or TRK-820 co … More uld be highly recommended for the cure of drug dependence.On the other hand, I investigated that intra-nucleus accumbens injection of a selective protein kinase C(PKC) inhibitor chelerythrine chloride blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. Under these conditions, the immunoreactivity of the cytosolic phosphorylated-PKC in the limbic forebrain region including the N.Acc.was slightly, but significantly increased in methamphetamine-sensitized rats. Furthermore, it should be mentioned that the protein level of NR2B subunit was significantly increased in membrane preparations of the limbic forebrain obtained from methamphetamine-sensitized rats. Moreover, methamphetamine produced prolonged PKC-dependent astrocytic activation, whereas morphine caused a reversible activation of astrocytes in in vivo and in vitro study. In conclusion, the present study provides novel evidence that the development of sensitization to the methamphetamine-induced rewarding effects may be, at least in part, linked to the increased level of PKC, NR2B subunit and PKC-dependent astrocytic activation by methamphetamine in rodents. Less

重复使用甲基苯丙胺导致甲基苯丙胺诱导的多巴胺释放及其相关行为的增强。这种现象称为致敏或逆转耐受。在这项研究中，我证明了N-甲基-D-天冬氨酸（NMDA）受体拮抗剂艾芬地尔和κ-阿片受体激动剂TRK-820对啮齿动物对甲基苯丙胺诱导的奖励效应和多巴胺释放的敏感性的发展的影响。本研究采用条件性位置偏爱实验和在体微透析技术。艾芬地尔或TRK-820的治疗取消了甲基苯丙胺诱导的位置偏爱的增强与甲基苯丙胺重复治疗。此外，核内的神经元（N. Acc.）TRK-820的注射阻断了由重复甲基苯丙胺处理诱导的对N.Acc中多巴胺释放的敏化的发展。这些发现有力地表明，用艾芬地尔或TRK-820治疗， ...更多信息强烈推荐用于治疗药物依赖。另一方面，我研究了伏隔核内注射选择性蛋白激酶C（PKC）抑制剂氯化白屈菜红碱可以阻止重复甲基苯丙胺治疗诱导的N.Acc中多巴胺释放敏感化的发展。在这些条件下，在边缘前脑区，包括N.ACC的胞浆磷酸化PKC的免疫反应性略有增加，但在甲基苯丙胺致敏大鼠显着。此外，应该提到的是，NR 2B亚单位的蛋白质水平显着增加，在边缘前脑的膜制备获得的甲基苯丙胺致敏大鼠。此外，在体内和体外研究中，甲基苯丙胺产生延长的PKC依赖性星形胶质细胞活化，而吗啡引起星形胶质细胞的可逆活化。总之，本研究提供了新的证据表明，甲基苯丙胺诱导的奖励效应的敏感化的发展可能，至少部分地，与增加的PKC，NR 2B亚基和PKC依赖的星形胶质细胞激活甲基苯丙胺在啮齿类动物。少