Mu receptors and ethanol/dopamine interactions

Mu 受体和乙醇/多巴胺相互作用

• 批准号: 6936044
• 负责人: RUEBEN A. GONZALES
• 金额: $ 33.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-12 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936044
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; basal ganglia; behavior test; behavioral /social science research tag; dopamine; dopamine antagonists; dosage; electrophysiology; ethanol; gamma aminobutyrate; gene deletion mutation; genetic models; genetically modified animals; laboratory mouse; microinjections; naloxone; neurochemistry; neuropharmacology; neurotoxicology; opioid receptor; protein structure function; receptor expression; reinforcer; voltage /patch clamp

DESCRIPTION (provided by applicant): The neurochemical and cellular mechanisms that contribute to the control of ethanol drinking behavior are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, e.g., the opiate peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opiate receptor antagonist, but its mechanism is not known in detail. Mu opiate receptors are anatomically located in the ventral tegmental area (VTA) and are known to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opiate receptor subtypes has not been firmly established. Our preliminary studies show that mu opiate receptors are involved in the mechanism by which ethanol stimulates dopamine release in the ventral striatum, one of the terminal areas of the mesolimbic system. We propose to determine whether genetic deletion or irreversible blockade of the mu opiate receptor alters the dose-response curve for ethanol-stimulated dopamine release in the ventral striatum (aim 1). The genetic model we propose to use will be congenic mu receptor knockouts and wild-type controls that have been established on a C57BL/6 background. These studies will be complemented by investigation of effects of irreversible blockade of mu receptors with the use of naloxonazine. We also will determine whether the deletion of the mu receptor or irreversible blockade alters ethanol consumption using a two bottle choice procedure (aim 2). Moreover, we propose to determine whether mu receptors in the ventral tegmental area or the ventral striatum are involved in the inhibitory effects of loss of mu receptor function on ethanol stimulated dopamine release (aim 3). This will be done by microinjection of naloxonazine into either area and measuring the ethanol response. The role of mu receptors in the control of VTA-dopamine neurons will be examined using electrophysiological measures of cellular and synaptic activity in GABAergic interneurons (aim 4). These studies will utilize both the genetic and pharmacological approaches as described above. Together, the proposed experiments will elucidate the role of mu opiate receptors in the modulation of mesolimbic dopamine activity by ethanol.

描述（由申请人提供）：有助于控制乙醇饮酒行为的神经化学和细胞机制尚未完全了解，但人们已经假设多巴胺参与中脑边缘系统一段时间了。已知许多神经化学系统调节中脑边缘多巴胺系统的活性，例如阿片肽及其受体。纳曲酮是临床上用于减少酒精中毒复发的有效药物，是一种广谱阿片受体拮抗剂，但其机制尚不清楚。 Mu 阿片受体在解剖学上位于腹侧被盖区 (VTA)，已知通过抑制 GABA 中间神经元来控制 VTA 多巴胺神经元活性。然而，这种机制在乙醇调节多巴胺释放中的作用以及特定阿片受体亚型的作用尚未确定。我们的初步研究表明，mu 阿片受体参与乙醇刺激腹侧纹状体（中脑边缘系统的终端区域之一）释放多巴胺的机制。我们建议确定 mu 阿片受体的基因缺失或不可逆阻断是否会改变腹侧纹状体中乙醇刺激的多巴胺释放的剂量反应曲线（目标 1）。我们建议使用的遗传模型将是在 C57BL/6 背景上建立的同源 mu 受体敲除和野生型对照。这些研究将通过使用纳洛嗪不可逆阻断 mu 受体的影响进行研究来补充。我们还将使用两瓶选择程序确定 mu 受体的缺失或不可逆阻断是否会改变乙醇消耗（目标 2）。此外，我们建议确定腹侧被盖区或腹侧纹状体中的 mu 受体是否参与 mu 受体功能丧失对乙醇刺激的多巴胺释放的抑制作用（目标 3）。这将通过将纳洛嗪显微注射到任一区域并测量乙醇反应来完成。 mu 受体在 VTA-多巴胺神经元控制中的作用将通过 GABA 能中间神经元细胞和突触活动的电生理学测量来检查（目标 4）。这些研究将利用如上所述的遗传和药理学方法。总之，拟议的实验将阐明 mu 阿片受体在乙醇调节中脑边缘多巴胺活性中的作用。