Mu receptors and ethanol/dopamine interactions

Mu 受体和乙醇/多巴胺相互作用

• 批准号: 7106386
• 负责人: RUEBEN A. GONZALES
• 金额: $ 32.69万
• 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/7106386
• 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）：尚不完全了解有助于控制乙醇饮用行为的神经化学和细胞机制，但多巴胺在中溶胶系统中的参与已有一段时间了。已知许多神经化学系统可以调节中唇多巴胺系统的活性，例如阿片肽及其受体。纳曲酮是一种用于减少酒精中毒复发的临床有效药物，是一种广泛的鸦片受体拮抗剂，但其机制尚不清楚。 MU鸦片受体在解剖学上位于腹侧盖区（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。但是，这种机制在乙醇对多巴胺释放的调节以及特定的鸦片受体亚型的作用中的作用尚未牢固确定。我们的初步研究表明，MU Opiate受体参与了乙醇刺激腹侧纹状体中多巴胺释放的机制，腹侧纹状体是中溶液系统的末端区域之一。我们建议确定MU鸦片受体的遗传缺失或不可逆的阻塞是否改变了腹侧纹状体中乙醇刺激的多巴胺释放的剂量反应曲线（AIM 1）。我们建议使用的遗传模型将是在C57BL/6背景下建立的先天MU受体敲除和野生型对照。这些研究将通过使用纳洛甲胺对不可逆封锁受体的影响的影响进行补充。我们还将确定使用两个瓶子选择程序的删除MU受体或不可逆的封锁是否会改变乙醇的消耗（AIM 2）。此外，我们建议确定腹侧换段区域或腹侧纹状体中的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（AIM 3）。这将通过将纳洛甲胺显微注射到任何一个区域并测量乙醇反应来完成。 MU受体在控制VTA多巴胺神经元控制中的作用将使用GABA能中神经元中细胞和突触活性的电生理学测量进行检查（AIM 4）。如上所述，这些研究将利用遗传和药理方法。总之，提出的实验将阐明乙醇在调节乙醇中脱甲贝胺活性中的MU鸦片受体的作用。