COBRE: UMMC: ROLE OF MU-OPIOID SYSTEM IN METHAMPHETAMINE SENSITIZATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。甲基苯丙胺是目前美国滥用最广泛的毒品之一。长期使用这种药物可能会产生行为敏感化。中枢神经系统中的中脑边缘多巴胺系统被认为在行为敏感化的发展中起着关键作用。然而，多巴胺的活性受到其他传递的调节，并且在中脑边缘通路中阿片能、γ-氨基丁酸(GABA)能和多巴胺能神经元之间存在密切的相互作用。Mu阿片系统可能通过含有GABA的神经元来调节多巴胺的活动。已知苯丙胺可诱导中脑边缘系统内源性阿片肽的释放和细胞外多巴胺的增加。阿片受体拮抗剂可以预防苯丙胺诱导的多巴胺和行为多动。因此，我们推测Mu-阿片系统通过调节GABA和多巴胺系统参与了甲基苯丙胺敏化的发展。为了验证这一假说并阐明Mu阿片系统在甲基苯丙胺敏化中的作用，我们计划使用Mu阿片受体基因敲除小鼠来检测在甲基苯丙胺敏化发展过程中行为和神经化学物质(阿片能、多巴胺和GABA能活性)的变化。为了更好地了解阿片能、GABA能和多巴胺能系统在甲基苯丙胺敏化发展过程中的相互作用，本研究将使用对这些系统的药理学操作。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Methamphetamine is currently one of the most widely abused drugs in the United States. Long term use of the drug may produce behavioral sensitization. The mesolimbic dopamine system in the central nervous system is thought to play a critical role in the development of behavioral sensitization. However, dopamine activity receives regulation from other transmissions and the existence of close interactions among opioidergic, gamma-aminobutyric acid (GABA)ergic, and dopaminergic neurons in the mesolimbic pathway is well established. The mu-opioid system may modulate dopamine activity via GABA-containing neurons. It is known that amphetamine induces release of endogenous opioid peptides and an increase in extracellular dopamine in the mesolimbic system. Opioid receptor antagonists can prevent amphetamine-induced dopamine and behavioral hyperactivity. Therefore, we hypothesized that mu-opioid system is involved in the development of methamphetamine sensitization through modulation of GABA and dopamine systems. To test the hypothesis and to clarify the role of mu-opioid system in methamphetamine sensitization, we plan to use mu-opioid receptor knockout mice to detect changes in behaviors and neurochemicals (opioidergic, dopaminergic, and GABAergic activity) during the development of methamphetamine sensitization. For a better understanding of the interactions among opioidergic, GABAergic, and dopaminergic systems in the development of methamphetamine sensitization, pharmacological manipulations on these systems will be used in the study.