Individual differences in stimulant reinforcement as a function of DRD2 allele

描述（由申请人提供）：虽然精神运动兴奋剂的滥用潜力已被充分证明，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等位基因更普遍，特别是在兴奋剂滥用者中。据我们所知，尚未研究的是，预期被确定为DRD2 A1等位基因携带者或非携带者的个体，对兴奋剂强化效应的敏感性如何不同。该提案是根据NIDA的RFA DA-09-016提交的，“行为药理学和遗传学：翻译和靶向个体差异”。该研究的主要目的是前瞻性地研究携带和不携带该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），并完成与药物滥用易感性相关的基线测量（例如，人口统计学，冲动，寻求感觉）。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应的明显个体差异，参与者将有反复选择d-AMP或安慰剂的机会。使用多种d-AMP剂量（5,10,20mg / 70kg）将使我们比单一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危险因素与等位基因状态之间的关系。我们假设等位基因携带者相对于非携带者会有更高的冲动和感觉寻求。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等位基因的可能性之间存在正线性关联。在二次分析中，我们将对不同等位基因状态的受试者进行分组，并检查选择数据，假设d-AMP选择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。在拟议的研究中，我们将前瞻性地研究d-AMP的增强是否作为DRD2等位基因状态的函数而变化。从这项研究中获得的知识可以促进我们对个体对精神运动兴奋剂强化作用的易感性差异的理解，从而有益于公共卫生。总的来说，成功开发一个人类实验室模型，以严格调查个人对常见滥用药物的强化效应的脆弱性，这将是我们在理解、预防和治疗药物滥用方面迈出的重要一步。

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.