DOPAMINERGIC BRAIN FUNCTION IN ALCOHOLICS

酗酒者的多巴胺能大脑功能

• 批准号: 2894045
• 负责人: NORA D VOLKOW
• 金额: $ 36.41万
• 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/2894045
• 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：我们假设多巴胺的GABA能调节减少， (DA)酗酒者的活动导致大脑区域功能异常 接受DA能传出神经和对刺激的反应加重， 增加DA，这增强了乙醇的增强性能， 强迫性饮酒的出现。 在本提案中，我们 将使用PET来评估两个独立的酗酒者的DA系统， 研究;一个是在休息时评估DA系统，另一个是在 药理学激活 我们假设，在静息状态下， 酗酒者不会在DA细胞本身中观察到，但在突触后 在DA刺激反应期间， 将被强调。 为了评估静态DA系统，我们将使用多个跟踪器方法， 在同一主题中评估传播中涉及的不同因素 DA信号; DA末端（使用[11 C]雷氯必利，DA D2受体配体） 和与DA系统连接的区域的活性（使用2-脱氧 2-[18 F]氟-D-葡萄糖（[18 F]FDG））在早期和晚期酒精 戒断 为了评估DA系统在药理学激活过程中的作用， 将测量对哌醋甲酯（MP）的反应， 通过抑制DA转运体来抑制突触DA。 检察官的反应 系统将使用PET间接测量MP对 [11 C]雷氯必利结合和脑葡萄糖代谢。 因为检察官 与[11 C]雷氯必利竞争D2受体，这种策略使我们能够 评估MP诱导的DA相对变化，而代谢测量 可以让我们评估大脑对多巴胺变化的反应 浓度. 我们的工作假设是，解毒的酗酒者：（1） 静息时D2受体可用性降低，但DA受体可用性未降低 在长期戒酒后仍然存在的转运蛋白。 变化 D2受体将与额叶皮层活动减少有关。 新陈代谢. (2)对增加DA的刺激有加重的反应 浓度（这将显示为随着代谢和DA变化的增加， MP）。 拟议的研究将能够确定DA系统是否异常， 酗酒者;这些异常的功能后果和 解毒的效果。 这些知识将提供一个重要的背景， 了解酒精中毒的神经化学机制