Translational Research of Cocaine, Striatum, and Impulsivities

可卡因、纹状体和冲动的转化研究

• 批准号: 8307523
• 负责人: Marc N Potenza
• 金额: $ 90.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307523
• 关键词: Alcohol or Other Drugs use; Clinical; Cocaine; Cocaine Dependence; Complex; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine Agonists; Dorsal; Etiology; Functional Magnetic Resonance Imaging; Gene Expression; Image; Impulsivity; Individual; Investigation; Laboratories; Lead; Link; Measures; Mediating; Neurobiology; Neurocognitive; Neurons; Positron-Emission Tomography; Prevention strategy; Public Health; Rattus; Research; Self Administration; Series; Translational Research; Viral Physiology; addiction; improved; information gathering; nonhuman primate; novel; prevent; public health relevance; radiotracer; relating to nervous system; response; translational study; treatment strategy

DESCRIPTION (provided by applicant): Despite intensive research efforts, cocaine dependence (CD) remains a prevalent and costly disorder whose precise etiology remains poorly understood and thus poorly prevented and treated. Impulsivity has been increasingly recognized as an important factor that may predispose individuals to addiction as well as be modified by substance use to promote further engagement. Impulsivity constitutes a complex, multi-faceted construct that has been shown to involve separate domains of choice and response impulsivity. The striatum has been implicated in translational studies of addiction, with important contributions from both ventral and dorsal components to specific aspects of addiction. Striatal function has also been preliminarily linked to aspects of impulsivity. However, the manners in which aspects of impulsivity and regions of striatal function relate to one another and CD are poorly understood in this exploratory center, we seek to investigate these relationships in a series of tightly integrated, cohesive translational investigations. Specifically, CD and matched control subjects will participate in fMRI investigations using tasks of choice and response impulsivity to probe the underlying neural correlates as related to CD. These subjects will also be imaged with a novel, highly selective D2/D3 dopamine receptor agonist radiotracer, [11C] PHNO to investigate striatal dopamine function. Through a clinical core, the same subjects will be evaluated on a broad range of clinical, neurocognitive, and laboratory measures including challenges to assess stimulant effects on choice and response impulsivity and cocaine self administration in CD subjects. As such, the fMRI and PET projects will investigate the relationships between the neural measures and the clinical ones. Two additional projects will utilize the same choice and response impulsivity tasks and [11C] PHNO PET assessments in non-human primates and rats. These projects investigate cocaine influence on choice and response impulsivity and gather information on electrophysiological neuronal function and viral-mediated gene expression effects that are not possible in CD subjects. Together, data from these highly integrated, translational studies should advance our understanding of CD and help target the development of more effective prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Cocaine dependence is a significant public health problem. An improved understanding of the underlying neurobiology that might best be achieved through integrated translational research has significant potential to lead to breakthroughs that could prevent or effectively treat this devastating disorder.

描述（由申请人提供）：尽管进行了深入的研究工作，但可卡因依赖（CD）仍然是一种普遍且昂贵的疾病，其精确的病因仍然很糟糕，因此预防和治疗也很差。冲动性越来越多地被认为是一种重要因素，可能使人易于成瘾，并通过使用物质使用以促进进一步的参与度进行修改。冲动性构成了一个复杂的多面构建体，已显示出涉及选择和反应冲动的单独域。纹状体与成瘾的翻译研究有关，腹侧和背部成分对成瘾的特定方面的重要贡献。纹状体功能也已与冲动性方面相关。但是，在这个探索性中心，对冲动性和纹状体功能区域方面和纹状体功能区域的举止彼此相关，我们试图在一系列紧密整合的，具有凝聚力的翻译研究中研究这些关系。具体而言，CD和匹配的对照受试者将使用选择和反应冲动性的任务参与fMRI研究，以探测与CD相关的潜在神经相关性。这些受试者还将通过一种新型的高度选择性D2/D3多巴胺受体激动剂放射性抗体[11C] PHNO进行成像，以研究纹状体多巴胺的功能。通过临床核心，将对相同的受试者进行对广泛的临床，神经认知和实验室措施进行评估，包括评估对CD受试者中选择和反应冲动性和可卡因自我给药的刺激作用的挑战。因此，功能磁共振成像和宠物项目将研究神经测量与临床措施之间的关系。其他两个项目将利用相同的选择和反应冲动任务以及[11C]非人类灵长类动物和大鼠的[11C] PHNO PET评估。这些项目研究可卡因对选择和反应冲动的影响，并收集有关电生理神经元功能以及病毒介导的基因表达效应的信息，这些效应在CD受试者中是不可能的。总之，来自这些高度综合的，翻译研究的数据应提高我们对CD的理解，并有助于针对更有效的预防和治疗策略的发展。 公共卫生相关性：可卡因依赖是一个重大的公共卫生问题。对可能通过综合翻译研究最能实现的基本神经生物学的了解，可以提高突破性，从而可以预防或有效治疗这种毁灭性疾病。