Individual differences in stimulant reinforcement as a function of DRD2 allele

描述（由申请人提供）：虽然精神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应的反应存在显著差异。遗传因素被假设为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，前瞻性地确定为DRD 2 A1等位基因携带者或非携带者的个体，对兴奋剂的增强作用的敏感性可能有所不同。本提案是根据NIDA的RFA DA-09-016“行为药理学和遗传学：翻译和针对个体差异”提交的。主要目的将是前瞻性地调查是否有和没有等位基因的个人在响应经典的精神兴奋剂，d-安非他明（d-AMP）的不同。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相关的基线测量（例如，人口统计学、冲动性、感觉寻求）。然后，我们将使用人类实验室模型来严格评估个体对d-AMP强化作用的敏感性。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强化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）将允许我们比单剂量更容易地检测组差异（例如，剂量-效应曲线的偏移）。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。次要目的1：我们将研究在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了兴奋剂滥用严重程度与个体具有A1等位基因的概率之间的正线性关联。在二次分析中，我们将在等位基因状态下对受试者进行分类，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。在拟议的研究中，我们将前瞻性地检查d-AMP增强是否随DRD 2等位基因状态而变化。从这项研究中获得的知识可能有益于公共卫生，通过推进我们对精神兴奋剂强化作用的个体差异的理解。总的来说，成功开发一个人类实验室模型，严格调查个人对常见滥用药物的强化作用的脆弱性，将是我们在理解、预防和治疗药物滥用方面迈出的重要一步。 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容易滥用药物有关。在拟议的研究中，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利于公共卫生，促进我们对精神兴奋剂强化效应脆弱性的个体差异的理解，并改善我们更普遍地理解、预防和治疗药物滥用的努力。

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.