Basic research for the treatment of psychological dependence on methamphetamine

反复使用甲基苯丙胺可增强甲基苯丙胺诱导的多巴胺释放及其相关行为。这种现象被称为致敏或反向耐受。在本研究中，我展示了n -甲基- d -天冬氨酸（NMDA）受体拮抗剂伊芬prodil和κ-阿片受体激动剂TRK-820对甲基苯丙胺诱导的奖励效应敏化发展和多巴胺释放的影响。本研究采用条件位置偏好范式和体内微透析试验。用伊芬地尔或TRK-820治疗可消除反复使用甲基苯丙胺后甲基苯丙胺诱导的位置偏好增强。此外，在伏隔核内注射TRK-820阻断了反复甲基苯丙胺诱导的伏隔核多巴胺释放敏化的发展。这些结果强烈表明，强烈建议使用伊芬地尔或TRK-820 co .治疗药物依赖。另一方面，我研究了在伏隔核内注射一种选择性蛋白激酶C（PKC）抑制剂chelerythrine chloride，阻断了反复甲基苯丙胺治疗诱导的n.c.对多巴胺释放的敏化发展。在这些条件下，甲基苯丙胺致敏大鼠的边缘前脑区包括n.a.c .的胞浆磷酸化pkc的免疫反应性略有增加，但显著增加。此外，需要指出的是，在甲基苯丙胺致敏大鼠的边缘前脑膜制剂中，NR2B亚基的蛋白水平显著升高。此外，在体内和体外研究中，甲基苯丙胺产生了长时间的pkc依赖性星形细胞激活，而吗啡则引起了星形细胞的可逆激活。总之，本研究提供了新的证据，证明甲基苯丙胺诱导的奖励效应敏化的发展可能至少部分与甲基苯丙胺在啮齿类动物中PKC、NR2B亚基和PKC依赖性星形细胞激活水平的增加有关。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