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: 8321367
• 负责人: J. DAVID JENTSCH
• 金额: $ 31.58万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321367
• 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; 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; 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; genome wide association study; 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. PUBLIC HEALTH RELEVANCE: Behavior addictions, including the abuse of or dependence on drugs of abuse, cause substantial personal and social costs. Unfortunately, prevention and cessation treatments are few and of limited efficacy. With that in mind, understanding the genetic architecture of risk for addictions raises new avenues, not just for quantifying liability, but for developing biomarkers that can be the target of prevention trials. Moreover, identification of the molecular genetic mediators of addictions raises new potential treatment targets.

描述（由申请人提供）：抑制或抑制预强行为（“冲动”的一种表现）的困难与人类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，而成瘾的发展会侵蚀涉及冲动控制的大脑机制。该应用涉及前一个问题（冲动的遗传变异会导致成瘾），并测试了冲动反应和对滥用药物的增强作用的敏感性在遗传上相关的观点，这意味着一组共同的基因组机制会影响两者。该假设将使用一组经典近交和重组近交小鼠——杂交小鼠多样性面板进行直接测试。我们将在大约 100 种菌株中检查可卡因的自我给药情况，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；通过这样做，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对可卡因强化进行全基因组扫描。完成这些实验目标将为我们提供一个机会，对冲动性和冲动性这一观点进行首次直接测试。 成瘾样表型受到共同的遗传控制，并将产生关于影响这些行为特征的独立和共同遗传位点的全新信息。了解行为成瘾易感性的生物机制可能会阐明新的风险生物标志物，这些生物标志物可用于评估干预措施的质量和影响，并为化学和非化学依赖性新疗法的开发提供信息。 公共卫生相关性：行为成瘾，包括滥用或依赖滥用药物，会造成巨大的个人和社会成本。不幸的是，预防和戒烟治疗很少，而且效果有限。考虑到这一点，了解成瘾风险的遗传结构提出了新的途径，而不仅仅是量化责任， 而是为了开发可以作为预防试验目标的生物标志物。此外，身份识别 成瘾的分子遗传介质的研究提出了新的潜在治疗目标。