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

将 d-安非他明主观效应的时间差异与 DRD2 和 DAT 联系起来

• 批准号: 9050120
• 负责人: Christopher Thomas Smith
• 金额: $ 5.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050120
• 关键词: ANKK1 gene; Accounting; Acute; Adult; Affect; Amphetamines; Anterior; Area; Behavioral; Binding; Biological; Biological Markers; Brain; CDH13 gene; Corpus striatum structure; DRD2 gene; Data; Development; Dextroamphetamine; Dopamine; Dopamine D2 Receptor; Drug Addiction; Drug Delivery Systems; Drug Kinetics; Euphoria; Fellowship; Future; Genes; Genetic; Genetic Polymorphism; Goals; Impulsivity; Individual; Individual Differences; Ingestion; Intake; Lead; Link; Measurable; Measures; Mediating; Midbrain structure; Nature; Neurotransmitters; Nucleotides; Oral; Outcome; Participant; Personality; Personality Traits; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Psychostimulant dependence; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Site; Speed; System; Testing; Time; Variant; Work; absorption; addiction; career; cingulate cortex; discounting; dopamine system; dopamine transporter; drug of abuse; endophenotype; experience; externalizing behavior; genetic analysis; genetic approach; genetic variant; genome wide association study; neurochemistry; pre-clinical; psychostimulant; public health relevance; response; trait

 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.

 描述（由申请人提供）：虽然滥用药物向大脑的传递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引起的快感和喜好速度的个体差异，以及这种差异是否反映在大脑、个性或遗传水平上。然而，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特征存在显着差异。本奖学金提出的研究将使用正电子发射断层扫描 (PET) 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-安非他明诱导的多巴胺释放），并将这些 PET 测量与 d-安非他明的积极主观反应（药物兴奋和喜好）的差异联系起来，特别强调 积极主观药物作用达到峰值的时间。此外，拟议的研究将评估多巴胺系统功能的个体差异以及 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，我们将研究多巴胺相关基因中常见的多态性以及钙粘蛋白 13 基因中的信号核苷酸多态性的作用，该多态性先前在全基因组关联研究中发现与 d-苯丙胺的积极主观作用相关。该研究计划的目标是更好地了解个体差异，这些差异会带来精神兴奋剂成瘾的潜在风险，包括多巴胺的快速上升和服用药物后主观高/喜欢的增加。申请人的长期目标是确定 多巴胺系统功能的差异如何与行为内表型水平的成瘾风险相关，包括主观药物高/喜欢达到峰值的时间、寻求新奇和冲动（包括急剧的时间贴现）。该奖学金将帮助申请人发展 他拥有测量多巴胺系统变化（通过 PET 和遗传方法）的专业知识，并为他作为一名独立调查员为多巴胺在成瘾风险、外化行为和其他通常与毒瘾相关的特征中的作用的独立研究者做好了富有成效的职业生涯的准备。