Genetic Influences on Inhibitory Control and Cocaine Sensitivity

描述(由申请人提供)：抑制或抑制强效行为的困难(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表型有关。这种关系被认为是双向的；冲动很可能是增加的一个易感因素，而成瘾的发展侵蚀了涉及冲动控制的大脑机制。这项应用涉及前一种担忧(冲动的可遗传变异会导致上瘾)，并测试冲动反应和对滥用药物强化效应的敏感性在遗传上相关的想法，这意味着一套共同的基因组机制影响两者。这一假设将使用一组经典的近交系和重组近交系小鼠--杂交小鼠多样性小组--直接进行检验。我们将检查来自专家小组的大约100个菌株的可卡因自我给药，这些菌株已经在反向学习测试中被研究过抑制冲动反应的能力；通过这样做，我们将能够测量这些特征之间的遗传相关性。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，进行第一次直接测试的想法，冲动和 类似成瘾的表型受到共同的基因控制，并将在影响这些行为特征的独立和共同遗传位点上产生全新的信息。了解指示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记物，这些标记物可用于评估干预的质量和影响，并为开发治疗化学和非化学依赖的新方法提供信息。

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.