The Mu1-opioid receptors and ethanol-stimulated mesolimbic dopamine release

乙醇是一种被广泛滥用的药物，具有巨大的社会经济影响，但乙醇的机制 增援力量还不清楚。中脑边缘系统，包括多巴胺能通路， 腹侧被盖区（VTA）的腹侧纹状体，提出发挥主要作用，乙醇 加固.中脑边缘多巴胺活性受阿片肽系统（包括 内源性阿片肽配体及其相应的受体亚型），并受 外源性鸦片纳洛酮是一种阿片受体拮抗剂，用于临床管理 酒精中毒，但其机制并不牢固。然而，已知纳洛酮引起 中脑边缘多巴胺减少纳洛酮是一种非选择性阿片受体拮抗剂， 因此，确定更具选择性的阿片拮抗剂对中脑边缘多巴胺的作用是重要的。 release.这将使我们能够表征单个阿片受体亚型对乙醇的贡献 增强，并且还使得能够开发可能用于治疗的更具选择性的阿片样物质拮抗剂。 酒精中毒的临床治疗最近的证据表明，在腹侧被盖区和腹侧被盖区的u-阿片受体， 腹侧纹状体可能参与强化和中脑边缘多巴胺释放。我们的长期目标是 以确定乙醇-阿片样物质-多巴胺相互作用的机制。假设乙醇会导致 在腹侧被盖区和腹侧纹状体中β-内啡肽的增加，导致u-阿片受体的激活 在这些地区的人群，这导致中脑边缘多巴胺释放增加，这可能导致 加强。在μ-阿片受体亚型中，μ-阿片受体是研究最多的。具体 本研究的目的是确定腹侧被盖区和腹侧纹状体中的u1-阿片受体是否 参与了乙醇刺激的多巴胺释放所提出的实验涉及测定 选择性阻断腹侧被盖区和腹侧纹状体u1阿片受体亚型对乙醇- 刺激中脑边缘多巴胺释放C57 BL/6 J小鼠将用于所有实验，透析液 使用体内微透析测定多巴胺和乙醇浓度。本研究结果 将增加我们对乙醇刺激阿片介导的多巴胺释放机制的理解。 这些结果也可能导致开发更有效的药理学药物， 酒精中毒的管理。

Ethanol is a widely abused drug with a huge socio-economic impact, yet the mechanisms of ethanol reinforcement are still not clear. The mesolimbic system, which includes the dopaminergic pathway from the ventral tegmental area (VTA) to the ventral striatum, is proposed to play a major role in ethanol reinforcement. Mesolimbic dopamine activity is modulated by the opioid peptide system (which includes endogenous opioid peptide ligands and their corresponding receptor subtypes), and is affected by exogenous opiates. Naltrexone, an opioid receptor antagonist, is used in the clinical management of alcoholism but its mechanism is not firmly established. However, it is known that naltrexone causes a decrease in mesolimbic dopamine. Naltrexone is a non-selective opioid receptor antagonist, and it is therefore important to determine the effects of more selective opioid antagonists on mesolimbic dopamine release. This will enable us to characterize the contributions of individual opioid receptor subtypes to ethanol reinforcement, and also enable the development of more selective opioid antagonists for possible use in the clinical management of alcoholism. Recent evidence suggests that u-opioid receptors in both the VTA and ventral striatum may be involved in reinforcement and mesolimbic dopamine release. Our long term goal is to determine the mechanism of ethanol-opioid-dopamine interaction. Ethanol is hypothesized to cause an increase of (3-endorphin, in both the VTA and ventral striatum, leading to an activation of u-opioid receptor populations in these regions, which results in an increase in mesolimbic dopamine release, which may lead to reinforcement. Of the u-opioid receptor subtypes, the ul-opioid receptor is the most studied. The specific aims of this study are to determine if the u1-opioid receptors in the VTA and the ventral striatum are involved in ethanol-stimulated dopamine release. The proposed experiments involve determination of the effect of selective blockade of u1 opioid receptor subtype in the VTA and ventral striatum, on ethanol- stimulated mesolimbic dopamine release. C57BL/6J mice will be used in all experiments, and dialysate dopamine and ethanol concentrations will be determined using in vivo microdialysis. The results of this study will increase our understanding of the mechanism of ethanol-stimulated opioid mediated dopamine release. The results could also lead to the development of more effective pharmacological agents for the management of alcoholism.