Genetic Influences on Inhibitory Control and Cocaine Sensitivity

描述（由申请方提供）：难以抑制或抑制优生行为（“冲动”的一种表现）与人类中的兴奋剂和酒精滥用和依赖以及动物模型中的成瘾样表型有关。这种关系被认为是双向的;冲动可能是成瘾的一个责任因素，成瘾的发展侵蚀了与冲动控制有关的大脑机制。本申请涉及前一个问题（冲动性的遗传变异导致成瘾），并测试了冲动反应和对滥用药物的强化作用的敏感性在遗传上相关的想法，这意味着一组共同的基因组机制影响两者。将使用一组经典近交系和重组近交系小鼠-杂交小鼠多样性小组直接检验这一假设。我们将检查可卡因自我管理的约100个菌株，这些菌株已经在逆转学习测试中研究了它们抑制冲动反应的能力;这样做，我们将能够测量这些性状之间的遗传相关性。我们还将使用收集的数据集进行可卡因强化的全基因组扫描。这些实验目标的完成将提供一个机会，对冲动性和 成瘾样表型受共同的遗传控制，并将产生关于影响这些行为特征的独立和共同遗传基因座的全新信息。了解行为成瘾易感性的生物学机制可能会阐明新的风险生物标志物，可用于评估干预措施的质量和影响，以及为化学和非化学依赖性的新治疗方法的开发提供信息。

DESCRIPTION (provided by applicant): Difficulty suppressing or inhibiting pre-potent behaviors (one manifestation of 'impulsivity') has been linked with stimulant and alcohol abuse and dependence in humans and with addiction- like phenotypes in animal models. This relationship is thought to run in both directions; impulsivity is likely a liability factor for addctions, and the development of addiction erodes brain mechanisms involved in impulse control. This application relates to the former concern (that heritable variation in impulsivity leads to addictions) and test the idea that impulsive responding and sensitivity to the reinforcing effects of drugs of abuse are genetically correlated, meaning that a common set of genomic mechanisms influence both. This hypothesis will be tested directly, using a panel of classic inbred and recombinant inbred mice - the hybrid mouse diversity panel. We will examine cocaine self-administration in ~100 strains from the panel that will already have been studied for their ability to inhibit impulsive responding in a reversal learning test; in doing so, we will be ble to measure the genetic correlation between these traits. We will also conduct whole-genome scans for cocaine reinforcement using the gathered datasets. Completion of these experimental aims will offer an opportunity to undertake the first direct tests of the idea that impulsivity and addiction-like phenotypes are under common genetic control and will generate completely new information on the independent and common genetic loci that influence these behavioral traits. Understanding the biological mechanisms that index susceptibility to behavior addictions may illuminate new biomarkers for risk that can be used to assess the quality and impact of interventions, as well as to inform the development of new treatments for chemical and non- chemical dependencies.