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

Mu1-阿片受体和乙醇刺激的中脑边缘多巴胺释放

• 批准号: 7229138
• 负责人: Martin O Job
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229138
• 关键词: behavioral /social science research tag; corpus striatum; dopamine; ethanol; high performance liquid chromatography; laboratory mouse; microdialysis; microinjections; naloxone; neurochemistry; neuropharmacology; neuroregulation; neurotransmitter transport; opioid receptor; predoctoral investigator; protein structure function; receptor expression; reinforcer; tegmentum

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.

描述（由申请人提供）：乙醇是一种广泛滥用的药物，具有巨大的社会经济影响，但乙醇强化的机制仍不清楚。中脑边缘系统，其中包括从腹侧被盖区（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）调节，并受外源性阿片剂的影响。纳洛酮是一种阿片受体拮抗剂，用于酒精中毒的临床治疗，但其机制尚未确定。然而，已知纳洛酮导致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受体拮抗剂对中脑边缘多巴胺释放的影响是重要的。这将使我们能够表征单个阿片受体亚型对乙醇强化的贡献，也使开发更具选择性的阿片受体拮抗剂，可能用于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纹状体的μ-阿片受体可能参与强化和中脑边缘多巴胺的释放。我们的长期目标是确定乙醇-阿片类药物-多巴胺相互作用的机制。假设乙醇引起腹侧被盖区和腹侧纹状体中β-内啡肽的增加，导致这些区域中μ-阿片受体群体的激活，这导致中脑边缘多巴胺释放的增加，这可能导致强化。在μ-阿片受体亚型中，μ 1-阿片受体是研究最多的。本研究的具体目的是确定是否在腹侧被盖区和腹侧纹状体的μ-阿片受体参与乙醇刺激的多巴胺释放。拟议的实验涉及确定选择性阻断腹侧被盖区和腹侧纹状体中的μ 1阿片受体亚型对乙醇刺激的中边缘多巴胺释放的影响。在所有实验中将使用C57 BL/6J小鼠，并且将使用体内微透析来确定透析液多巴胺和乙醇浓度。本研究的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。研究结果还可能导致开发更有效的药物来治疗酒精中毒。