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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 甲基苯丙胺是目前美国最广泛滥用的药物之一。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化的发展中起关键作用。然而，多巴胺活性接受其他传输的调节，并且在中脑边缘通路中阿片样物质、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。μ-阿片系统可以通过含GABA的神经元调节多巴胺活性。已知安非他明诱导内源性阿片肽的释放和中脑边缘系统中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症。因此，我们假设μ阿片系统通过调节GABA和多巴胺系统参与甲基苯丙胺致敏的发展。 为了验证这一假设并阐明μ阿片系统在甲基苯丙胺致敏中的作用，我们计划使用μ阿片受体敲除小鼠检测甲基苯丙胺致敏过程中行为和神经化学物质（阿片能、多巴胺能和GABA能活性）的变化。为了更好地了解阿片类、GABA能和多巴胺能系统在甲基苯丙胺致敏作用中的相互作用，本研究将对这些系统进行药理学操作。

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.