Basic research for the treatment of psychological dependence on methamphetamine

甲基苯丙胺反复治疗可增强甲基苯丙胺诱导的多巴胺释放及其相关行为。这种现象被称为敏化或反向耐受。在本研究中，我观察了N-甲基-D-天冬氨酸受体拮抗剂异苯地尔和κ阿片受体激动剂TRK820对甲基苯丙胺诱导的奖赏效应和多巴胺释放的增敏作用。本研究采用条件性位置偏爱范式和体内微透析实验。异丙苯地尔或TRK-820可阻断重复甲基苯丙胺治疗后对甲基苯丙胺位置偏爱的增强作用。此外，伏隔核内核团(N.Acc.)注射TRK-820可阻断重复甲基苯丙胺处理引起的大鼠神经元多巴胺释放的敏化。这些发现有力地表明，用异丙苯地尔或trk-820co…治疗另一方面，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，阻断了对重复甲基苯丙胺处理所致的多巴胺释放的敏化发展。在此条件下，甲基安非他明致敏大鼠边缘前脑区(包括下丘脑)胞浆磷酸化PKC的免疫反应性略有增加，但显著增强。此外，值得一提的是，在甲基苯丙胺致敏大鼠边缘前脑膜标本中，NR2B亚单位的蛋白水平显著增加。此外，在体内和体外研究中，甲基苯丙胺引起长时间依赖PKC的星形胶质细胞激活，而吗啡引起星形胶质细胞的可逆激活。总之，本研究提供了新的证据，表明对甲基苯丙胺诱导的奖赏效应的敏化可能至少部分地与甲基苯丙胺增加啮齿动物的PKC、NR2B亚单位水平和PKC依赖的星形胶质细胞激活有关。较少

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