Individual differences in stimulant reinforcement as a function of DRD2 allele

描述(申请人提供)：虽然精神运动兴奋剂的滥用潜力已经得到很好的证明，但不同的人在对兴奋剂的强化和主观影响的反应方面存在显著差异。遗传因素被认为影响药物滥用的易感性，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，预期被识别为DRD2 A1等位基因携带者或非携带者的个体，在对兴奋剂增强效应的敏感性方面可能会有什么不同。本提案是针对NIDA的RFA DA-09-016《行为药理学和遗传学：转化和针对个体差异》提出的。主要目的将是前瞻性地调查有和没有等位基因的个体对经典的精神运动兴奋剂d-苯丙胺(d-AMP)的反应是否不同。将招募等位基因携带者(N=30)和非携带者(N=30)，并完成与药物滥用易感性(例如，人口统计学、冲动、感觉寻求)相关的基线测量。然后，我们将使用人体实验室模型来严格评估个体对d-AMP增强效应的敏感性。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强化效果的明显个体差异，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/70千克)将使我们能够比单一剂量更容易地检测出组内差异(例如，剂量-效应曲线的变化)。我们假设等位基因携带者将比非携带者表现出更大的对d-AMP的偏好。次要目标1：我们将检查摄入时评估的其他危险因素与等位基因状态之间的关系。我们假设，与非携带者相比，等位基因携带者将具有更高的冲动和感觉寻求。次要目标2：先前的研究已经回顾发现，兴奋剂滥用的严重程度与个体携带A1等位基因的概率之间存在正向线性关联。在二次分析中，我们将研究对象的等位基因状态，并检查选择数据，假设d-AMP选择的百分比与个体拥有该等位基因的概率之间存在线性关系。总而言之，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对兴奋剂滥用的脆弱性有关。在这项拟议的研究中，我们将前瞻性地研究d-AMP的增强是否随着DRD2等位基因状态的变化而变化。从这项研究中获得的知识可能会促进我们对精神运动兴奋剂增强效应的易感性的个体差异的理解，从而有益于公共健康。总体而言，成功开发人体实验室模型，严格调查个人对常见滥用药物强化效应的脆弱性，将代表着我们在了解、预防和治疗药物滥用的努力中向前迈出了重要的一步。 公共卫生相关性：个人对药物的反应差异很大，这些差异可能与他们对药物滥用的脆弱性有关。在这项拟议的研究中，我们将前瞻性地检查一个人的多巴胺受体基因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会促进我们对精神运动兴奋剂增强效应的易感性的个体差异的理解，并改进我们更广泛地了解、预防和治疗药物滥用的努力，从而有益于公众健康。

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.