Translational Research of Cocaine, Striatum, and Impulsivities

描述（由申请人提供）：尽管进行了大量的研究工作，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，因此预防和治疗也很差。人们越来越认识到冲动是一个重要因素，它可能使个体容易上瘾，并可以通过物质使用来改变以促进进一步的参与。冲动构成了一个复杂的、多方面的结构，已被证明涉及选择和反应冲动的不同领域。纹状体与成瘾的转化研究有关，腹侧和背侧成分对成瘾的特定方面都有重要贡献。纹状体功能也已初步与冲动的某些方面相关。然而，在这个探索中心，人们对冲动性和纹状体功能区域相互关联以及 CD 的方式知之甚少，我们试图通过一系列紧密整合、有凝聚力的转化研究来研究这些关系。具体来说，CD 和匹配的对照受试者将使用选择任务和反应冲动参与功能磁共振成像研究，以探究与 CD 相关的潜在神经相关性。这些受试者还将使用新型、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，将对相同受试者进行广泛的临床、神经认知和实验室测量评估，包括评估对 CD 受试者的选择和反应冲动以及可卡因自我给药的刺激作用的挑战。因此，fMRI 和 PET 项目将研究神经测量与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利用相同的选择和反应冲动任务以及 [11C] PHNO PET 评估。这些项目调查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和病毒介导的基因表达效应的信息，这些信息在 CD 受试者中是不可能的。总之，来自这些高度整合的转化研究的数据应该可以增进我们对克罗恩病的理解，并有助于制定更有效的预防和治疗策略。 公共卫生相关性：可卡因依赖是一个重大的公共卫生问题。最好通过综合转化研究来提高对潜在神经生物学的理解，这具有巨大的潜力，可以带来预防或有效治疗这种破坏性疾病的突破。

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.