Genetic basis of methamphetamine intake

甲基苯丙胺摄入量的遗传基础

• 批准号: 8732881
• 负责人: TAMARA J. RICHARDS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732881
• 关键词: Accident and Emergency department; Accounting; Aggressive behavior; Agonist; Amphetamines; Animal Model; Animals; Behavior; Behavioral Genetics; Brain Injuries; Breeding; Buprenorphine; Candidate Disease Gene; Chromosomes, Human, Pair 10; Clinical; Code; Congenic Strain; Consumption; Crime; Cues; Data; Development; Diagnosis; Disease; Drug Controls; Drug Use Disorder; Drug abuse; Ephedrine; Epidemic; Evaluation; Family; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Variation; Genotype; Goals; Health; Health Services Research; Hospitals; Human; Individual; Intake; International; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Maps; Measures; Medical center; Methadone; Methamphetamine; Methamphetamine dependence; Methods; Mexico; Military Personnel; Modeling; Molecular; Mus; Narcotic Controls; Opiate Addiction; Opioid; Opioid Receptor; Oral; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Population; Post-Traumatic Stress Disorders; Prevention; Procedures; Production; Proteins; Pseudoephedrine; Psychological reinforcement; Psychotic Disorders; Quantitative Trait Loci; Receptor Gene; Relapse; Research; Rewards; Risk; Seizures; Self Administration; Sequence Analysis; Single Nucleotide Polymorphism; System; Taste Perception; Terrorism; Testing; Time; Trauma; United Nations; United States; United States Food and Drug Administration; Update; Veterans; Visit; Western Blotting; Work; addiction; base; combat; congenic; cost; drinking; endophenotype; follow-up; genetic analysis; methamphetamine abuse; model development; mouse model; mu opioid receptors; preference; progenitor; programs; public health relevance; receptor function; reinforcer; research and development; screening; statistics; stressor; tool; trait; trend

DESCRIPTION (provided by applicant): The abuse of illegal drugs poses a worldwide problem, with a multitude of negative individual and societal consequences. Addiction to methamphetamine (MA) damages the brain, can induce psychosis, and is associated with crime and increased aggression. Military personnel, including Veterans and their families, have been identified as among key populations requiring special support to deal with their drug abuse problems. Genetic animal models for investigating risk for MA use and mechanisms that underlie risk and escalating use are lacking. This application describes research focused on a genetic mouse model for human methamphetamine (MA) use and on the identification of genetic factors and specific mechanisms that influence genetic risk for MA abuse. To be utilized are (1) unique genetic tools that consist of lines of mice selectively bred for high and low MA drinking (the MADR lines) and of interval specific congenic strains to be used for finer mapping of a gene(s) that influences MA intake; and (2) a newly developed operant oral MA self-administration method that has been used to validate the MADR lines as a genetic model that shows differential sensitivity to the reinforcing effects of MA. This program of research will develop a model of genetically-determined escalating, binge-like MA intake. It will also follow up the results of quantitative trat locus (QTL) mapping, which identified a locus on mouse chromosome 10 that accounts for ~50% of the genetic variance associated with differential MA intake, by completing finer mapping and sequence analysis that will allow progress to be made in identifying genes and gene networks that influence genetic risk for MA addiction. Preliminary data support the importance of mu-opioid receptors in this risk and pharmacological and molecular studies will be completed to further test the importance of this mechanism. In addition, molecular analyses will explore other potential candidate mechanisms and knockout mice and pharmacological approaches for druggable targets will be used to follow-up promising mechanisms. There are 3 specific aims: (1) examine genetically-determined patterns of MA intake, escalation, binge-like intake, and reinstatement. Potential differences in sensitivity to reinforcement by natural rewards will also be examined as part of this aim; (2) use an existing panel of interval specific congenic strains to more finely map the chromosome 10 QTL; measure genetically correlated traits in these congenics to test the hypothesis that a common genetic region on mouse chromosome 10 influences MA drinking and the correlated trait; (3) complete qPCR, sequence and Western blot analyses, after fine mapping of the chromosome 10 QTL, for genes that could impact MA drinking; use these data to identify specific mechanisms that should be tested for their impact on MA intake, using knockout and pharmacological approaches. Functional analysis of the mu- opioid receptor in the MADR lines, one candidate gene in the chromosome 10 interval, will also be completed. This work has the potential for developing a needed genetic animal model of high MA intake that takes advantage of existing genetic risk in the development of this model. In addition, the study of opioid system involvement dovetails nicely with ongoing clinical work that indicates concomitant changes in MA use in individuals receiving buprenorphine or methadone treatment (both opioid receptor agonists) for opiate dependence. Use of the genetic model will indicate whether animals at higher genetic risk for MA use are susceptible to opioid and other pharmacological interventions that are explored.

描述（由申请人提供）： 非法药物的滥用构成了一个世界性问题，给个人和社会带来了许多负面后果。甲基苯丙胺 (MA) 成瘾会损害大脑，可能诱发精神病，并与犯罪和攻击行为增加有关。包括退伍军人及其家人在内的军事人员已被确定为需要特别支持来解决药物滥用问题的关键人群。缺乏用于调查 MA 使用风险以及风险和升级使用的机制的遗传动物模型。该申请描述了针对人类甲基苯丙胺 (MA) 使用的遗传小鼠模型以及识别影响 MA 滥用遗传风险的遗传因素和具体机制的研究。要利用的是 (1) 独特的遗传工具，其中包括针对高 MA 饮酒量和低 MA 饮酒量选择性培育的小鼠品系（MADR 品系）以及间隔特定的同系品系，用于更精细地绘制影响 MA 的基因图谱摄入量； (2) 一种新开发的操作性口服 MA 自我给药方法，已用于验证 MADR 系作为遗传模型，显示出对 MA 增强作用的不同敏感性。该研究计划将开发一个由基因决定的逐步增加的、类似暴饮暴食的 MA 摄入量模型。它还将跟踪定量 trat 基因座 (QTL) 作图的结果，通过完成更精细的作图和序列分析，该结果确定了小鼠 10 号染色体上的一个基因座，该基因座占与差异 MA 摄入相关的遗传方差的约 50%。在识别影响 MA 成瘾遗传风险的基因和基因网络方面仍需取得进展。初步数据支持 mu-阿片受体在这一风险中的重要性，并将完成药理学和分子研究，以进一步测试该机制的重要性。此外，分子分析将探索其他潜在的候选机制，敲除小鼠和可药物靶点的药理学方法将用于后续有希望的机制。有 3 个具体目标：(1) 检查由基因决定的 MA 摄入、升级、暴饮暴食和恢复模式。对自然奖励强化的敏感性的潜在差异 作为这一目标的一部分也将受到审查； (2) 使用现有的区间特异性同源菌株组来更精细地定位 10 号染色体 QTL；测量这些同源基因的遗传相关性状，以检验小鼠 10 号染色体上的共同遗传区域影响 MA 饮酒和相关性状的假设； (3) 在对 10 号染色体 QTL 进行精细定位后，对可能影响 MA 饮用的基因进行完整的 qPCR、序列和蛋白质印迹分析；使用这些数据来确定应使用敲除和药理学方法测试其对 MA 摄入影响的具体机制。 MADR 系中 mu-阿片受体（10 号染色体区间的候选基因）的功能分析也将完成。这项工作有可能开发出所需的高 MA 摄入量遗传动物模型，该模型利用了该模型开发中现有的遗传风险。此外，阿片类药物系统参与的研究与正在进行的临床工作非常吻合，该临床工作表明接受丁丙诺啡或美沙酮（均为阿片类受体激动剂）治疗的阿片依赖个体的 MA 使用发生了相应的变化。遗传模型的使用将表明具有较高 MA 使用遗传风险的动物是否对阿片类药物和其他正在探索的药物干预措施敏感。