Genetic Influences on Inhibitory Control and Cocaine Sensitivity

描述（由申请人提供）：难以抑制或抑制强效前行为（“冲动”的一种表现）与人类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不利因素，而成瘾的发展侵蚀了与冲动控制有关的大脑机制。这一应用与前一种担忧（冲动的遗传变异导致成瘾）有关，并验证了冲动反应和对滥用药物的强化效应的敏感性在基因上是相关的，这意味着一套共同的基因组机制对两者都有影响。这一假设将被直接检验，使用一组经典的近交系和重组的近交系小鼠——杂交小鼠多样性小组。我们将检查来自该小组的约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研究了它们抑制冲动反应的能力；这样，我们就能测量这些性状之间的遗传相关性。我们还将利用收集到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，对冲动和冲动的概念进行第一次直接测试

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.