Translational Research of Cocaine, Striatum, and Impulsivities

描述(申请人提供)：尽管进行了密集的研究工作，但可卡因依赖(CD)仍然是一种普遍且代价高昂的疾病，其确切病因仍然缺乏了解，因此预防和治疗不力。冲动已经越来越被认为是一个重要因素，它可能使个人容易上瘾，并被物质使用改变以促进进一步的参与。冲动是一个复杂的、多方面的结构，已被证明涉及选择和反应冲动的不同领域。纹状体参与了成瘾的翻译研究，腹侧和背侧成分对成瘾的特定方面都有重要贡献。纹状体功能也初步被认为与冲动有关。然而，在这个探索中心，冲动性和纹状体功能区域之间相互联系的方式和CD知之甚少，我们试图通过一系列紧密结合的、有凝聚力的翻译研究来研究这些关系。具体地说，CD和匹配的对照组受试者将参与使用选择任务和反应冲动的fMRI研究，以探索与CD相关的潜在神经关联。这些受试者还将接受一种新型的、高选择性的D2/D3多巴胺受体激动剂放射性示踪剂[11C]PHNO的成像，以研究纹状体的多巴胺功能。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，包括评估刺激对CD受试者的选择和反应冲动的影响以及可卡因自身给药的挑战。因此，功能磁共振成像和正电子发射计算机断层扫描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身上使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功能和病毒介导的基因表达效应的信息，这在CD受试者中是不可能的。总之，来自这些高度整合的转化性研究的数据应该会促进我们对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。通过综合翻译研究最好地实现对潜在神经生物学的理解，具有巨大的潜力，可以导致可以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.