Organismal and Genetic Networks in Drug Reward and Reinforcement

描述(申请人提供)：可卡因成瘾对受害者的生活、他们的家庭和整个社会的影响是令人震惊的。决定个人从最初使用可卡因转变为滥用和上瘾的具体因素包括 这在很大程度上是未知的，但遗传学的作用已经确立。因此，识别增加滥用可卡因易感性的特定基因一直是研究界相当努力的领域。在人类群体中确定与成瘾相关的遗传基因座的尝试取得了一些成功，但由于缺乏环境控制、遗传异质性、需要大样本和伦理问题而变得复杂。基因稳定的小鼠群体已被证明对研究复杂的人类疾病如成瘾很有用。虽然小鼠永远不会复制定义人类疾病状态的全部特征，但有一些常用的行为模型被认为忠实地代表了成瘾的关键特征。大多数滥用药物在急性给药时会引起精神运动刺激，而且最初对药物的敏感性与随后使用和滥用的风险增加有关。因此，对可卡因反应的运动激活经常被用来作为小鼠成瘾相关行为的模型。众所周知，近交系小鼠对可卡因的运动反应差异很大，这证明了遗传学在这一复杂行为中的作用。最近，一个密集的SNP面板已经被开发出来，它允许确定近亲交配小鼠品系的单倍型结构。这些SNP数据，以及近交系的行为数据，可以用来进行全基因组关联图谱(Gwas)，以识别与可卡因运动反应相关的基因组座位。我们最近完成了对可卡因诱导的运动反应的45个近交系品系的调查，并确定了影响行为的多个遗传位点。该应用程序的目标是在标准杂交(F2)群体中复制这些QTL，并使用近交系的单倍型信息来缩小QTL间隔并识别候选基因。我们还建议通过测量基因敲除系的行为和互补测试来测试一组候选基因。最后，我们建议检查表型分布两端的近交系菌株，试图揭示导致可卡因最初运动敏感性并可能增加成瘾风险的生物机制。

DESCRIPTION (provided by applicant): The impact of cocaine addiction on the lives of those who suffer from it, their families and society as a whole is staggering. The specific factors that determine an individuals' risk of transitioning from initial cocaine use to abuse and addiction are largely unknown but a role for genetics has been established. Therefore, identification of specific genes that increase susceptibility to abuse cocaine has been an area of considerable effort in the research community. Attempts to identify genetic loci involved in addiction liabilityin human populations have met with some success but are complicated by lack of environmental control, genetic heterogeneity, the need for large sample sizes and ethical concerns. Genetically stable mouse populations have proven useful for the study of complex human diseases like addiction. While mice will never replicate the entire spectrum of traits that define the human disease state, there are commonly used behavioral models that are believed to faithfully represent key features of addiction. Most drugs of abuse cause psychomotor stimulation when administered acutely and initial sensitivity to a drug has been associated with increased risk for subsequent use and abuse. Therefore, locomotor activation in response to cocaine is often used as a model for addiction-related behavior in mice. It has been known for some time that inbred strains of mice differ widely in their locomotor response to cocaine proving a role for genetics in this complex behavior. More recently, a dense SNP panel has been developed that allows for determination of haplotype structure in inbred mouse strains. These SNP data, along with inbred strain behavioral data, can be used to conduct genome-wide association mapping (GWAS) to identify genomic loci that are associated with cocaine locomotor response. We have recently completed a 45 inbred strain survey of cocaine-induced locomotor response and have identified multiple genetic loci that influence the behavior. The goal of this application is to replicate these QTL in standard intercross (F2) populations and use haplotype information from inbred strains to narrow QTL intervals and identify candidate genes. We also propose to test a set of candidate genes by measuring behavior in knockout lines and by complementation testing. Finally, we propose to examine inbred strains at the extreme ends of the phenotypic distribution in an attempt to uncover the biological mechanisms that contribute to initial locomotor sensitivity to cocaine and may increase risk for addiction.