Individual differences in stimulant reinforcement as a function of DRD2 allele

作为 DRD2 等位基因功能的刺激强化的个体差异

• 批准号: 7932770
• 负责人: STACEY C SIGMON
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932770
• 关键词: Alleles; Behavioral; Categories; Cocaine; DRD2 A1 Allele; DRD2 gene; Data; Dependence; Development; Dextroamphetamine; Diagnosis; Dopamine D2 Receptor; Dopamine Receptor; Dose; Double-Blind Method; Drug abuse; Drug usage; Esthesia; Exhibits; Genetic; Genetic Polymorphism; Genotype; Human; Impulsivity; Individual; Individual Differences; Intake; Knowledge; Laboratories; Literature; Measures; Methamphetamine; Methylphenidate; Modeling; Other Genetics; Participant; Patient Self-Report; Pharmaceutical Preparations; Placebos; Play; Prevalence; Probability; Procedures; Psychological reinforcement; Public Health; Recruitment Activity; Relative (related person); Research; Risk Factors; Role; Sampling; Series; Severities; Translating; base; behavioral pharmacology; demographics; design; drug reinforcement; improved; indexing; non-drug; preference; prevent; public health relevance; response; stimulant abuse

DESCRIPTION (provided by applicant): While the abuse potential of psychomotor stimulants has been well-demonstrated, there are marked differences across individuals in their response to the reinforcing and subjective effects of stimulants. Genetic factors are hypothesized to influence vulnerability to drug abuse and recent research suggests a greater prevalence of the D2 dopamine receptor A1 allele, in particular, among stimulant abusers. What has not been examined to our knowledge is how individuals, prospectively identified as DRD2 A1 allele carriers or noncarriers, may differ in their sensitivity to the reinforcing effects of stimulants. This proposal is submitted in response to NIDA's RFA DA-09-016, "Behavioral Pharmacology and Genetics: Translating and Targeting Individual Differences". The Primary Aim will be to prospectively investigate whether individuals with and without the allele differ in response to the classic psychomotor stimulant, d-amphetamine (d-AMP). Allele carriers (N=30) and noncarriers (N=30) will be recruited and complete baseline measures shown to be associated with vulnerability for drug abuse (e.g., demographics, impulsivity, sensation seeking). We will then use a human lab model to rigorously assess individual sensitivity to the reinforcing effects of d-AMP. Using a classic discrete-trial choice design shown in prior studies to demonstrate clear individual differences to the reinforcing effects of drugs, participants will have repeated opportunities to choose between d-AMP or placebo. Use of multiple d-AMP doses (5, 10, 20 mg/70 kg) will permit us to detect group differences more readily than a single dose would allow (e.g., shifts in dose-effect curves). We hypothesize that allele carriers will exhibit greater preference for d-AMP than noncarriers. Secondary Aim 1: We will examine associations between the other risk factors assessed at intake and allele status. We hypothesize that allele carriers will have elevated impulsivity and sensation seeking relative to noncarriers. Secondary Aim 2: Prior studies have retrospectively found a positive linear association between stimulant abuse severity and probability that an individual has the A1 allele. In secondary analyses, we will collapse subjects across allele status and examine choice data, hypothesizing a linear relationship between percent of d-AMP choices and probability that an individual has the allele. In summary, individuals vary widely in their response to psychomotor stimulants and these differences may be associated with their vulnerability to stimulant abuse. In the proposed study, we will prospectively examine whether d-AMP reinforcement varies as a function of DRD2 allele status. Knowledge gained from this study may benefit public health by advancing our understanding of individual differences in vulnerability to the reinforcing effects of psychomotor stimulants. Overall, the successful development of a human lab model for rigorously investigating individuals' vulnerability to the reinforcing effects of commonly-abused drugs would represent a significant step forward in our efforts to understand, prevent and treat drug abuse. PUBLIC HEALTH RELEVANCE: Individuals vary widely in their response to drugs and these differences may be associated with their vulnerability to drug abuse. In the proposed study, we will prospectively examine whether an individual's dopamine receptor genotype may predict their sensitivity to d-amphetamine reinforcement. Knowledge gained from this study may benefit public health by advancing our understanding of individual differences in vulnerability to the reinforcing effects of psychomotor stimulants and improving our efforts to understand, prevent and treat drug abuse more generally.

描述（由申请人提供）：虽然精神运动兴奋剂的滥用潜力得到了很好的证明，但个人在对兴奋剂的增强和主观效果的反应方面存在明显的差异。假设遗传因素会影响对药物滥用的脆弱性，而最近的研究表明，D2多巴胺受体A1等位基因的患病率更大，尤其是在刺激滥用者中。尚未对我们的知识进行检查的是，被前瞻性地识别为DRD2 A1等位基因携带者或非载流子的个体如何在对兴奋剂的增强作用的敏感性上有所不同。该建议是根据NIDA的RFA DA-09-016，“行为药理学和遗传学：翻译和靶向个体差异”提交的。主要目的是前瞻性地研究具有和不具有等位基因的个体在响应经典的精神运动刺激剂D-amphetamine（D-AMP）方面是否有所不同。等位基因载体（n = 30）和非驾驶员（n = 30）将被招募，并显示出与药物滥用脆弱性有关的完整基线测量（例如，人口统计学，冲动性，寻求感觉）。然后，我们将使用人类实验室模型严格评估对D-AMP增强作用的个人敏感性。使用先前研究中显示的经典离散选择设计设计，以证明药物增强作用的明显个性差异，参与者将有一再的机会在D-AMP或安慰剂之间进行选择。使用多种DAMP剂量（5、10、20 mg/70 kg）将使我们能够比单剂量更容易检测组差异（例如，剂量效应曲线的变化）。我们假设等位基因载体比非驾驶者更偏爱D-AMP。次要目标1：我们将研究以摄入量评估的其他风险因素与等位基因状态的关联。我们假设等位基因载体相对于非载体的冲动和感觉越来越高。次要目的2：先前的研究回顾性地发现，刺激性滥用的严重程度与个人具有A1等位基因的可能性之间存在正线性关联。在次要分析中，我们将跨等位基因状态的受试者崩溃并检查选择数据，假设D-AMP选择百分比和个人具有等位基因的概率之间的线性关系。总而言之，个体在对精神运动兴奋剂的反应方面差异很大，而这些差异可能与刺激性滥用的脆弱性有关。在拟议的研究中，我们将前瞻性地检查D-AMP增强是否随DRD2等位基因状态而变化。从这项研究中获得的知识可能会通过促进我们对脆弱性对心理兴奋剂增强作用的脆弱性的理解来使公共卫生受益。总体而言，成功地开发了一个人类实验室模型，以严格调查个体对普遍虐待药物的增强作用的脆弱性将代表我们在理解，预防和治疗药物滥用的努力方面迈出的重要一步。 公共卫生相关性：个人在对药物的反应方面差异很大，这些差异可能与他们易受滥用药物的脆弱性有关。在拟议的研究中，我们将前瞻性检查一个人的多巴胺受体基因型是否可以预测其对D-苯丙胺增强的敏感性。从这项研究中获得的知识可能会通过促进我们对脆弱性的个人差异的理解来使公共卫生受益，并改善我们更普遍地理解，预防和治疗药物滥用的努力。