Cocaine, Impulsivity, and PHNO Across Species

P20提案(项目2)的这一PET成像部分的主要目标是通过评估可卡因依赖(CD)受试者与健康对照组(HC)受试者的神经化学和行为差异，更好地了解与药物滥用相关的两种主要类型的冲动行为(冲动选择和冲动反应)的神经机制。我们建议比较有效的多巴胺D2/D3 PET激动剂配体[11C]PHN0在HC和CD的腹侧和背侧纹状体的结合潜力(特定目标1)，然后在评估冲动选择的任务和评估脉冲反应的任务(特定目标2)中，将结合潜力与fMRI(项目1)测量的事件相关BOLD活动相关联。我们进一步建议在大鼠和非人身上进行PET成像 并使用相同的认知/行为任务，将多巴胺D2/D3可用性的结果与冲动测量相关联。这是第一项专门设计的研究，旨在从行为和神经化学角度描述所有三个物种的冲动特征，并调查冲动与可卡因成瘾的关系。拟议的跨区域研究将提供 通过将临床和临床前的发现联系起来，以解决我们在了解影响成瘾倾向或对药物作用的易感性的因素、可能导致滥用和成瘾的神经生物学改变以及滥用药物可能如何影响暴露于药物后随时间变化的大脑系统和过程方面的主要差距，提供协同信息。通过使用神经成像技术(项目2)和复杂的功能和行为测量范例(项目2) 1和3)，通过整合病毒介导的基因表达研究(项目4)，我们可以开始在多个水平上更好地了解可卡因诱导的变化，包括分子基因、神经和行为水平。因此，这项拟议的研究具有重要的潜力，可以产生可以为人类可卡因成瘾的治疗发展提供信息的结果。

The main goal of this PET imaging section of the P20 proposal (Project 2) is to better understand the neural mechanisms associated with the two major types of impulsive behavior (impulsive choice and impulsive response) as related to drug abuse, by assessing the neurochemical and behavioral differences in cocaine dependent (CD) subjects as compared to healthy control (HC) subjects. We propose to compare the binding potential of [11C]PHN0, a potent dopamine D2/D3 PET agonist ligand, in ventral and dorsal striatum of HC and CD (Specific Aim 1), and then correlate the binding potential with the event-related BOLD activity measured by fMRI (Project 1) during a task assessing impulsive choice and during a task assessing impulsive response (Specific Aim 2). We further propose to conduct PET imaging in rats and non-human primates before and after cocaine exposure and correlate the results on the dopamine D2/D3 availability with impulsivity measures using the same cognitive/behavior tasks. This is the first study specifically designed to characterize impulsivity across all three species, both behaviorally and neurochemically, and to investigate the relationship of impulsivity to cocaine addiction. The proposed translafional research will provide synergisfic informafion by linking the clinical and preclinical findings to address a major gap in our understanding of the factors that influence addiction liability or vulnerability to the effects of drugs, the neurobiological alterations that may lead to abuse and addicfion, and how drugs of abuse may affect brain systems and processes that change over time after exposure to drugs. By employing neuroimaging technology (Project 2) paired with sophisficated functional and behavioral measurement paradigms (Project 1 & 3), and by integrating viral-mediated gene expression study (Project 4), we can begin to better understand the alterafion induced by cocaine at mulfiple levels, including the molecular genefic, neural and behavioral levels. Thus, the proposed study has significant potenfial to yield results that can be inform treatment development for cocaine addiction in humans.