Exploring regulation and function of Dopamine D3 Receptors in Alcohol Use Disorders. A [11C]-(+)-PHNO PET study

探索多巴胺 D3 受体在酒精使用障碍中的调节和功能。

• 批准号: 9034966
• 负责人: Bernard Le Foll
• 金额: $ 14.05万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034966
• 关键词: Affect; Aftercare; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Area; Binding; Brain; Brain imaging; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; DRD2 gene; Data; Development; Dopamine; Dose; Drug Targeting; Future; Globus Pallidus; Heavy Drinking; Human; Image; Injection of therapeutic agent; Lead; Measurement; Measures; Mediating; Medical; Midbrain structure; Neurotransmitters; Nicotinic Receptors; Outcome Measure; Phase; Plasma; Positron; Positron-Emission Tomography; Proteins; Protocols documentation; Raclopride; Regulation; Resolution; Rewards; Running; Smoking; System; Testing; Tobacco; Tracer; Ventral Striatum; addiction; alcohol effect; alcohol use disorder; cost; craving; dopamine D3 receptor; drug of abuse; image processing; improved; in vivo; interest; mesolimbic system; neurobiological mechanism; neurochemistry; novel; pre-clinical; pre-clinical research; preclinical study; primary outcome; public health relevance; putamen; radioligand; radiotracer; receptor; response; response biomarker; social; therapy development; tool; transmission process; treatment strategy; varenicline

 DESCRIPTION (provided by applicant): Alcohol is one of the most commonly used drugs of abuse. Alcohol acts on the mesolimbic dopamine system, a system that mediates the rewarding effects of this substance. Preclinical and clinical studies have revealed that varenicline, a drug targeting the nicotinic acetylcholine receptors (nAChRs), and currently used for smoking treatment, could also be useful for alcohol dependence treatment. Preliminary clinical trials have been promising, but direct evidence for the impact of varenicline on the mesolimbic dopamine system is lacking in humans. Imaging with positron emission tomography (PET) permits the measurement of neurochemicals in vivo. PET has become a powerful tool for neuroscientists to visualize and localize receptors and estimate the endogenous levels of neurotransmitters. The process of imaging requires the injection of a positron-emitting radiotracer (e.g. [11C]-raclopride or [11C]-(+)-PHNO) that binds to the protein of interest (e.g. DRD2/3) followed by the measurement of this binding using the PET scanner. To this date, no study has been performed to directly measure the influence of varenicline on dopamine transmission in human brains. The [11C]-(+)-PHNO radiotracer, developed at CAMH by the co-applicant Dr. Wilson, is a tracer that appears ideally suited to detect fluctuations in dopamine levels and is also the only radiotracer that allows for the measurement of transmission at the dopamine D3 receptor (DRD3) in human brain. Our primary outcome measure will be to determine the impact of varenicline on dopamine transmission using a brain imaging approach. [11C]-(+)-PHNO radiotracer binding will be analyzed in both DRD2/3 (caudate and putamen) and in DRD3-rich areas (ventral striatum, globus pallidus area, midbrain). The influence of chronic administration of varenicline will be evaluated under treatment and also after treatment phase. Analysis after a washout period will assess whether changes in dopamine return to normal, providing evidence that changes in this neurotransmitter are related to varenicline levels. These studies will improve our understanding of the action of varenicline in the human brain and could provide a marker of response allowing to determine which subjects could benefit from the use of varenicline to treat alcohol dependence.

 描述（由申请人提供）：酒精是最常用的滥用药物之一。酒精作用于中脑边缘多巴胺系统，该系统介导这种物质的奖励效应。临床前和临床研究表明，伐尼克兰，一种靶向烟碱乙酰胆碱受体（nAChR）的药物，目前用于吸烟治疗，也可以用于酒精依赖治疗。初步的临床试验是有希望的，但在人类中缺乏伐尼克兰对中脑边缘多巴胺系统影响的直接证据。正电子发射断层扫描（PET）成像允许测量体内的神经化学物质。PET已成为神经科学家可视化和定位受体以及估计内源性神经递质水平的有力工具。成像过程需要注射正电子发射放射性示踪剂（例如[11 C]-雷氯必利 或[11 C]-（+）-PHNO），然后使用PET扫描仪测量这种结合。到目前为止，还没有研究直接测量伐尼克兰对人脑中多巴胺传递的影响。由共同申请人Wilson博士在CAMH开发的[11 C]-（+）-PHNO放射性示踪剂是一种似乎非常适合检测多巴胺水平波动的示踪剂，也是唯一允许测量人脑中多巴胺D3受体（DRD 3）传输的放射性示踪剂。我们的主要结果测量将是使用脑成像方法确定伐尼克兰对多巴胺传递的影响。将在DRD 2/3（尾状核和壳核）和富含DRD 3的区域（腹侧纹状体、苍白球区域、中脑）中分析[11 C]-（+）-PHNO放射性示踪剂结合。将在治疗期间和治疗期后评价伐尼克兰长期给药的影响。洗脱期后的分析将评估多巴胺的变化是否恢复正常，提供证据表明这种神经递质的变化与伐尼克兰水平有关。这些研究将提高我们对伐尼克兰在人脑中作用的理解，并可以提供一种反应标志物，从而确定哪些受试者可以从使用伐尼克兰治疗酒精依赖中获益。