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

 描述（由申请人提供）：虽然滥用药物输送到大脑的速度被认为是其成瘾潜力的基础，但没有研究关注精神兴奋剂诱导的兴奋和喜好速度的个体差异，以及这种差异是否反映在大脑，个性或遗传学水平上。然而，我们研究小组的初步数据表明，口服d-安非他明的主观反应的时间分布存在显着差异。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样结合电位、多巴胺转运蛋白水平和d-苯丙胺诱导的多巴胺释放），并将这些PET测量与阳性主观反应的差异相关联（药物高和喜好），以d-安非他明，特别强调峰值积极的主观药物效果的时间。此外，拟议的研究将评估多巴胺系统功能的个体差异和d-安非他明的积极主观影响如何随健康成年人的人格特征和遗传多态性而变化。具体来说，我们将调查的作用，通常研究的多巴胺相关基因的多态性，以及在钙粘蛋白13基因的信号核苷酸多态性，以前发现与积极的主观效应的d-苯丙胺在全基因组关联研究。本研究计划的目标是更好地了解个体差异，这些差异赋予精神兴奋剂成瘾的潜在风险，包括多巴胺的快速上升和药物摄入后主观高度/喜好的增加。申请人的长期目标是确定 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，包括主观药物高/喜欢达到峰值的时间，新奇寻求和冲动（包括陡峭的时间折扣）。该奖学金将帮助申请人发展 在测量多巴胺系统的变化（通过PET和遗传方法）的专业知识，并准备他作为一个独立的研究人员多巴胺的作用成瘾风险，外化行为，和其他特征往往与药物成瘾的生产性职业生涯。

 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.