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

描述（由申请人提供）：乙醇是一种被广泛滥用的药物，具有巨大的社会经济影响，但乙醇强化的机制尚不清楚。中边缘系统，包括从腹侧被盖区（VTA）到腹侧纹状体的多巴胺能通路，被认为在乙醇强化中起主要作用。中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受体亚型）的调节，并受外源性阿片的影响。纳曲酮是一种阿片受体拮抗剂，用于酒精中毒的临床治疗，但其作用机制尚不明确。然而，众所周知，纳曲酮会导致中脑边缘多巴胺的减少。纳曲酮是一种非选择性阿片受体拮抗剂，因此确定更多选择性阿片受体拮抗剂对中脑边缘多巴胺释放的影响非常重要。这将使我们能够表征个体阿片受体亚型对乙醇强化的贡献，也使我们能够开发更多选择性阿片受体拮抗剂，用于酒精中毒的临床管理。最近的证据表明，VTA和腹侧纹状体中的mu-阿片受体可能参与强化和中边缘多巴胺释放。我们的长期目标是确定乙醇-阿片-多巴胺相互作用的机制。据推测，乙醇会导致VTA和腹侧纹状体中β -内啡肽的增加，导致这些区域的mu-阿片受体群体的激活，从而导致中边缘多巴胺释放增加，这可能导致强化。在mu-阿片受体亚型中，mu1-阿片受体是研究最多的。本研究的具体目的是确定VTA和腹侧纹状体中的mu1-阿片受体是否参与乙醇刺激的多巴胺释放。拟进行的实验包括确定选择性阻断VTA和腹侧纹状体mu1阿片受体亚型对乙醇刺激的中边缘多巴胺释放的影响。所有实验均采用C57BL/6J小鼠，通过体内微透析测定透析液多巴胺和乙醇浓度。本研究结果将增加我们对乙醇刺激阿片介导多巴胺释放机制的理解。该结果也可能导致开发更有效的药物治疗酒精中毒。

DESCRIPTION (provided by applicant): 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 mu-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 beta-endorphin, in both the VTA and ventral striatum, leading to an activation of mu-opioid receptor populations in these regions, which results in an increase in mesolimbic dopamine release, which may lead to reinforcement. Of the mu-opioid receptor subtypes, the mu1-opioid receptor is the most studied. The specific aims of this study are to determine if the mu1-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 mu1 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.