Linking Temporal Differences in d-Amphetamine Subjective Effects to DRD2 and DAT

 描述(申请人提供)：虽然滥用药物进入大脑的速度被认为是其成瘾潜力的基础，但还没有研究集中在心理刺激剂诱导的快感和喜好的速度的个体差异，以及这种差异是否反映在大脑、个性或遗传水平上。然而，来自我们研究小组的初步数据表明，口服d-苯丙胺的主观反应的时间分布存在显著差异。这项研究将使用正电子发射断层扫描(PET)来评估多巴胺系统功能的多个方面(纹状体和纹状体外D2样结合潜力、多巴胺转运体水平和d-苯丙胺诱导的多巴胺释放)，并将这些PET测量与d-苯丙胺的积极主观反应(药物兴奋和喜好)的差异联系起来，特别强调药物积极主观效应达到峰值的时间。此外，这项拟议的研究将评估在健康成年人中，多巴胺系统功能的个体差异和d-苯丙胺的积极主观影响如何随人格特征和基因多态而变化。具体地说，我们将在全基因组关联研究中调查通常研究的多巴胺相关基因的多态以及之前发现与d-苯丙胺的积极主观效应相关的钙粘蛋白13基因的信号核苷酸多态的作用。这项研究计划的目标是更好地了解个体差异，这些差异赋予了精神刺激性药物成瘾的潜在风险，包括多巴胺的快速上升和在吸食药物后主观上的高/喜欢增加。申请者的长期目标是确定 多巴胺系统功能的差异如何在行为内表型水平上与成瘾风险相关，行为内型包括主观药物高/喜欢高峰时间、新奇寻求和冲动(包括大幅时间折扣)。这项奖学金将帮助申请者发展 他拥有测量多巴胺系统变异的专业知识(通过PET和遗传方法)，并为作为多巴胺在成瘾风险、外化行为和其他经常与成瘾相关的特征中所起作用的独立调查者的富有成效的职业生涯做好准备。

 DESCRIPTION (provided by applicant): While the speed of delivery of drugs of abuse to the brain are thought to underlie their addictive potential, no research has focused on individual differences in speed of psychostimulant-induced high and liking and whether such differences are reflected at the level of the brain, personality, or genetics. Yet, preliminary data from our research group indicates there are dramatic differences in the temporal profile of subjective responses to oral d-amphetamine. The research proposed in this fellowship will use Positron Emission Tomography (PET) to assess multiple aspects of dopamine system function (striatal and extrastriatal D2-like binding potential, dopamine transporter levels, and d-amphetamine-induced dopamine release) and relate these PET measures to differences in positive subjective responses (drug high and liking) to d-amphetamine, with a particular emphasis on the timing of peak positive subjective drug effects. Furthermore, the proposed research will assess how individual differences in dopamine system function and the positive subjective effects of d-amphetamine vary with personality traits and genetic polymorphisms in healthy adults. Specifically, we will investigate the role of commonly studied polymorphisms in dopamine-related genes as well as a signal nucleotide polymorphism in the cadherin 13 gene previously found to be associated with the positive subjective effects of d-amphetamine in a genome wide association study. The goal of this research plan is to better understand individual differences that confer potential risk for psychostimulant addiction including a fast rise in dopamine and increased subjective high/liking after drug intake. The applicant's long-term goals are to identify how differences in dopamine system function relate to addiction risk at the level of behavioral endophenotypes including subjective drug high/liking time to peak, novelty seeking, and impulsivity (including steep temporal discounting). This fellowship will help the applicant develop expertise in measuring variation in the dopamine system (through PET and genetic approaches) and prepare him for a productive career as an independent investigator of dopamine's role in addiction risk, externalizing behaviors, and other traits often associated with drug addiction.