DOPAMINERGIC BRAIN FUNCTION IN ALCOHOLICS

酗酒者的多巴胺能大脑功能

• 批准号: 2862545
• 负责人: NORA D VOLKOW
• 金额: $ 34.5万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2862545
• 关键词: alcoholism /alcohol abuse; brain metabolism; clinical research; dopamine; dopamine receptor; dopamine transporter; gamma aminobutyrate; human subject; methylphenidate; neurochemistry; neuropharmacology; neurotransmitter metabolism; neurotransmitter transport; positron emission tomography; raclopride

DESCRIPTION: We hypothesize that decreased GABAergic modulation of dopamine (DA) activity in alcoholics results in abnormal function of brain regions receiving DAergic efferents and in accentuated responses to stimuli that increase DA which enhance the reinforcing properties of ethanol and favor the emergence of compulsive alcohol administration. In this proposal we will use PET to evaluate the DA system in alcoholics in two separate studies; one to evaluate the DA system at rest and the other during pharmacological activation. We hypothesize that at rest DA abnormalities in alcoholics will not be observed in the DA cells per se but on postsynaptic elements and on projection areas and that during DA stimulation responses will be accentuated. To evaluate the DA system at rest we will use a multiple tracer approach to assess in the same subject different elements involved in the propagation of the DA signal; DA terminals (using [11C]raclopride, a DA D2 receptor ligand) and the activity of regions connected with the DA system (using 2-deoxy 2-[18F]fluoro-D-glucose ([18F]FDG)) during early and late alcohol withdrawal. To evaluate the DA system during pharmacological activation we will measure the response to methylphenidate (MP), a drug that increases synaptic DA by inhibiting DA transporters. The responsivity of the DA system will be measured indirectly using PET to measure the effects of MP on [11C]raclopride binding and on brain glucose metabolism. Because DA competes with [11C]raclopride for the D2 receptors, this strategy enables us to assess relative changes in DA induced by MP, while the metabolic measure will allow us to assess the response of the brain to changes in DA concentration. Our working hypotheses are that detoxified alcoholics: (1) At rest have decreases in D2 receptor availability but not in DA transporters which persist after protracted alcohol withdrawal. Changes in D2 receptors will be associated with decreased activity in frontal metabolism. (2) Have accentuated responses to stimuli that increase DA concentration (which will show as increased metabolic and DA changes with MP). The proposed study will enable to determine if the DA system is abnormal in alcoholics; the functional consequences of these abnormalities and the effects of detoxification. This knowledge will provide an essential context for understanding the neurochemical mechanisms underlying alcoholism.

描述：我们假设减少了多巴胺的 GABA 能调节 酗酒者的（DA）活动导致大脑区域功能异常 接收 DAergic 传出信号并增强对刺激的反应 增加DA，增强乙醇的增强性能，有利于 强迫性饮酒的出现。 在这个提案中我们 将使用 PET 分两个单独评估酗酒者的 DA 系统 研究；一个用于评估静止状态下的 DA 系统，另一个用于评估 药理激活。 我们假设静息时 DA 异常 酗酒者不会在 DA 细胞本身中观察到，但会在突触后细胞中观察到 元素和投影区域以及 DA 刺激反应期间的元素 将会被强调。 为了评估静态 DA 系统，我们将使用多重示踪剂方法 评估同一主题中参与传播的不同元素 DA信号； DA 末端（使用[11C]雷氯必利，一种 DA D2 受体配体） 以及与 DA 系统连接的区域的活性（使用 2-脱氧 早期和晚期饮酒期间的 2-[18F]氟-D-葡萄糖 ([18F]FDG)) 撤回。 为了评估药理激活过程中的 DA 系统，我们 将测量对哌醋甲酯 (MP) 的反应，该药物可增加 通过抑制 DA 转运蛋白来调节突触 DA。 DA 的响应度 系统将使用 PET 间接测量，以测量 MP 对 [11C]雷氯必利结合和对脑葡萄糖代谢的影响。 因为DA 与 [11C]raclopride 竞争 D2 受体，这种策略使我们能够 评估 MP 引起的 DA 相对变化，而代谢测量 将使我们能够评估大脑对 DA 变化的反应 专注。 我们的工作假设是戒毒的酗酒者：（1） 休息时 D2 受体可用性降低，但 DA 没有降低 长期戒酒后仍持续存在的转运蛋白。 变化 D2 受体与额叶活动减少有关 代谢。 (2) 对增加 DA 的刺激有强烈的反应 浓度（这将表现为代谢增加和 DA 变化 国会议员）。 拟议的研究将能够确定 DA 系统是否存在异常 酗酒者；这些异常的功能后果和 排毒的作用。 这些知识将提供必要的背景 了解酗酒背后的神经化学机制。