Genetic Influences on Inhibitory Control and Cocaine Sensitivity

遗传对抑制控制和可卡因敏感性的影响

• 批准号: 8837594
• 负责人: J. DAVID JENTSCH
• 金额: $ 2.11万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837594
• 关键词: Alcohol abuse; Alcohols; Animal Model; Architecture; Behavior; Biological; Biological Markers; Brain; Chemicals; Chromosomes, Human, Pair 10; Cocaine; Data; Data Set; Decision Making; Dependence; Dependency; Development; Dose; Exposure to; Genetic; Genome; Genome Scan; Genomics; Human; Hybrids; Impairment; Impulsive Behavior; Impulsivity; Inbred Mouse; Inbreeding; Intervention; Link; Maps; Measures; Mediating; Mediator of activation protein; Mind; Molecular Genetics; Mus; Neurocognitive Deficit; Persons; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Prevention; Prevention trial; Psychological reinforcement; Psychopathology; Quantitative Trait Loci; Recombinants; Reversal Learning; Risk; Running; Sampling; Self Administration; Stimulus; Substance Use Disorder; Testing; Time; Variant; Withholding Treatment; Work; addiction; behavior influence; cognitive function; cost; drug of abuse; executive function; genetic linkage analysis; indexing; novel; preference; psychologic; response; social; stimulant abuse; trait

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.

描述（由申请人提供）：难以抑制或抑制预选前行为（“冲动性”的一种表现）与人类的兴奋剂和酗酒以及动物模型中的成瘾表型有关。人们认为这种关系朝两个方向发展。冲动性可能是加法的责任因素，而成瘾的发展则侵蚀了脉冲控制中涉及的大脑机制。该应用与以前的关注有关（冲动性的可遗传变化导致成瘾），并测试了这样的观念，即对滥用药物的增强作用的冲动反应和敏感性在遗传上相关，这意味着一组常见的基因组机制都会影响两者。该假设将直接使用一组经典的近交和重组小鼠 - 混合小鼠多样性面板进行检验。我们将检查面板中约有100个菌株中的可卡因自我给药，这些菌株已经被研究了，因为它们在逆转学习测试中抑制冲动反应的能力；这样一来，我们将衡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全基因组扫描以进行可卡因增强。这些实验目标的完成将提供一个机会，以对冲动性和 成瘾样的表型处于共同的遗传控制之下，并将在影响这些行为特征的独立和常见的遗传基因座上产生全新的信息。理解对行为成瘾的指标敏感性的生物学机制可能会阐明新的生物标志物，以实现可用于评估干预措施的质量和影响的风险，并为化学和非化学依赖性的新处理提供信息。