Translational Research of Cocaine, Striatum, and Impulsivities

描述（由申请人提供）：尽管进行了深入的研究，可卡因依赖（CD）仍然是一种普遍且昂贵的疾病，其确切的病因仍然知之甚少，因此很难预防和治疗。人们越来越认识到，冲动是一个重要因素，它可能使个人容易上瘾，也可能被物质使用所改变，以促进进一步的接触。冲动性构成了一个复杂的、多方面的结构，已被证明涉及选择冲动性和反应冲动性的不同领域。纹状体与成瘾的转化研究有关，其腹侧和背侧成分对成瘾的特定方面都有重要贡献。纹状体功能也初步与冲动有关。然而，在这个探索中心，冲动性和纹状体功能区域相互关联和CD的方式知之甚少，我们试图在一系列紧密整合的、有凝聚力的转化研究中调查这些关系。具体来说，CD和匹配的对照受试者将参与fMRI调查，使用选择和反应冲动任务来探测与CD相关的潜在神经相关性。这些受试者还将使用一种新型的、高选择性D2/D3多巴胺受体激动剂放射性示踪剂[11C] PHNO进行成像，以研究纹状体多巴胺功能。通过临床核心，将对相同的受试者进行广泛的临床，神经认知和实验室测量，包括评估兴奋剂对CD受试者选择和反应冲动和可卡因自我给药的影响的挑战。因此，fMRI和PET项目将研究神经测量和临床测量之间的关系。另外两个项目将在非人类灵长类动物和大鼠中使用相同的选择和反应冲动性任务和[11C] PHNO PET评估。这些项目研究了可卡因对选择和反应冲动的影响，并收集了在CD受试者中不可能的电生理神经元功能和病毒介导的基因表达效应的信息。总之，来自这些高度整合的转化研究的数据应该促进我们对乳糜泻的理解，并有助于制定更有效的预防和治疗策略。

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.