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: 7342865
• 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/7342865
• 关键词: Affect; Alcoholism; Clinical Management; Development; Dopamine; Dose; Economics; Endorphins; Ethanol; Goals; Individual; Intraperitoneal Injections; Lead; Ligands; Link; Measures; Mediating; Microdialysis; Microinjections; Midbrain structure; Mus; Naltrexone; Narcotic Antagonists; Opiates; Opioid; Opioid Peptide; Opioid Receptor; Pathway interactions; Pharmaceutical Preparations; Play; Population; Psychological reinforcement; Role; Saline; System; Testing; Thinking; Ventral Striatum; Ventral Tegmental Area; alcohol effect; alcohol reinforcement; endogenous opioids; in vivo; intraperitoneal; mesolimbic system; naloxonazine; neural circuit; receptor; research study

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.

乙醇是一种广泛滥用的药物，具有巨大的社会经济影响，但乙醇的机制 强化仍不明确。中脑边缘系统，包括来自大脑的多巴胺能通路 腹侧被盖区（VTA）到腹侧纹状体，被认为在乙醇中发挥主要作用 加强。中脑边缘多巴胺活性由阿片肽系统（包括 内源性阿片肽配体及其相应的受体亚型），并受到 外源性阿片类药物。纳曲酮是一种阿片受体拮抗剂，用于临床治疗 酒精中毒，但其机制尚不明确。然而，众所周知，纳曲酮会导致 中脑边缘多巴胺减少。纳曲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类拮抗剂对中脑边缘多巴胺的影响非常重要 发布。这将使我们能够表征个体阿片受体亚型对乙醇的贡献 强化，并且还能够开发更具选择性的阿片拮抗剂，以可能用于 酒精中毒的临床管理。最近的证据表明，VTA 和 腹侧纹状体可能参与强化和中脑边缘多巴胺释放。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。据推测，乙醇会导致 VTA 和腹侧纹状体中 (3-内啡肽) 的增加，导致 u-阿片受体激活 这些地区的人口，这导致中脑边缘多巴胺释放增加，这可能导致 来加固。在u-阿片受体亚型中，ul-阿片受体是研究最多的。具体的 本研究的目的是确定 VTA 和腹侧纹状体中的 u1-阿片受体是否 参与乙醇刺激的多巴胺释放。所提出的实验涉及确定 选择性阻断 VTA 和腹侧纹状体中的 u1 阿片受体亚型对乙醇的影响 刺激中脑边缘多巴胺的释放。所有实验均使用C57BL/6J小鼠，透析液 多巴胺和乙醇浓度将使用体内微透析测定。本研究结果 将增加我们对乙醇刺激阿片类药物介导的多巴胺释放机制的理解。 该结果还可能导致开发更有效的药物制剂 酗酒的管理。