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已得到充分证明，但个体对兴奋剂的强化和主观效果的反应存在显着差异。假设遗传因素会影响药物滥用的脆弱性，最近的研究表明 D2 多巴胺受体 A1 等位基因的患病率更高，特别是在兴奋剂滥用者中。据我们所知，尚未研究的是前瞻性地鉴定为 DRD2 A1 等位基因携带者或非携带者的个体对兴奋剂增强作用的敏感性可能有何不同。该提案是为了响应 NIDA 的 RFA DA-09-016“行为药理学和遗传学：转化和针对个体差异”而提交。主要目标是前瞻性研究具有和不具有等位基因的个体对经典精神运动兴奋剂 d-安非他明 (d-AMP) 的反应是否存在差异。将招募等位基因携带者 (N=30) 和非携带者 (N=30)，并完成与药物滥用脆弱性相关的基线测量（例如人口统计、冲动性、感觉寻求）。然后，我们将使用人体实验室模型来严格评估个体对 d-AMP 增强作用的敏感性。使用先前研究中显示的经典离散试验选择设计来证明药物增强作用的明显个体差异，参与者将有重复的机会在 d-AMP 或安慰剂之间进行选择。使用多个 d-AMP 剂量（5、10、20 mg/70 kg）将使我们比单剂量更容易检测组间差异（例如剂量效应曲线的变化）。我们假设等位基因携带者比非携带者对 d-AMP 表现出更大的偏好。次要目标 1：我们将检查摄入时评估的其他风险因素与等位基因状态之间的关联。我们假设等位基因携带者相对于非携带者具有更高的冲动性和感觉寻求。次要目标 2：先前的研究回顾性地发现兴奋剂滥用严重程度与个体具有 A1 等位基因的概率之间存在正线性关联。在二次分析中，我们将折叠等位基因状态的受试者并检查选择数据，假设 d-AMP 选择的百分比与个体具有等位基因的概率之间存在线性关系。总之，个体对精神运动兴奋剂的反应差异很大，这些差异可能与他们容易滥用兴奋剂有关。在拟议的研究中，我们将前瞻性地研究 d-AMP 强化是否随 DRD2 等位基因状态而变化。从这项研究中获得的知识可能会增进我们对精神运动兴奋剂增强作用脆弱性的个体差异的理解，从而有益于公共健康。总体而言，成功开发用于严格调查个人对常见滥用药物的强化作用的脆弱性的人体实验室模型，将代表我们在了解、预防和治疗药物滥用方面向前迈出了重要一步。 公共卫生相关性：个体对药物的反应差异很大，这些差异可能与他们容易滥用药物有关。在拟议的研究中，我们将前瞻性地研究个体的多巴胺受体基因型是否可以预测他们对 d-苯丙胺强化的敏感性。从这项研究中获得的知识可能有助于公众健康，增进我们对精神运动兴奋剂增强作用脆弱性的个体差异的理解，并改善我们更广泛地理解、预防和治疗药物滥用的努力。