Genetic basis of methamphetamine intake

甲基苯丙胺摄入量的遗传基础

• 批准号: 9339518
• 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/9339518
• 关键词: Accident and Emergency department; Aggressive behavior; Agonist; Amphetamines; Animal Genetics; Animal Model; Animals; Behavior; Behavioral; Brain Injuries; Buprenorphine; Candidate Disease Gene; Chromosome Mapping; Chromosomes, Human, Pair 10; Clinical; Code; Congenic Strain; Consumption; Crime; Cues; Data; Development; Diagnosis; Disease; Drug Controls; Drug Receptors; Drug Use Disorder; Drug abuse; Ephedrine; Epidemic; Evaluation; Factor Analysis; 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; Molecular Analysis; Mus; Narcotic Controls; Opiate Addiction; Opioid; Opioid Receptor; Oral; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; 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; Study models; System; Taste aversion; Terrorism; Testing; Time; Trauma; United Nations; United States; United States Food and Drug Administration; Update; Veterans; Visit; Western Blotting; Work; amphetamine use; base; combat; congenic; cost; drinking; endophenotype; follow-up; genetic analysis; methamphetamine abuse; methamphetamine effect; methamphetamine use; model development; mouse model; mu opioid receptors; preference; progenitor; programs; public health relevance; receptor function; reinforcer; research and development; screening; 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）： 滥用非法药物是一个世界性问题，给个人和社会带来了许多消极后果。甲基苯丙胺（MA）成瘾会损害大脑，可能诱发精神病，并与犯罪和攻击性增加有关。军事人员，包括退伍军人及其家属，被确定为需要特别支助以解决其药物滥用问题的关键人群。缺乏用于调查MA使用风险的遗传动物模型以及风险和逐步增加使用的机制。本申请描述了研究的重点是人类甲基苯丙胺（MA）使用的遗传小鼠模型，并确定遗传因素和影响MA滥用遗传风险的特定机制。要利用的是（1）独特的遗传工具，包括选择性繁殖的小鼠品系，用于高和低MA饮用（MADR系）和间隔特异性同源株系，用于影响MA摄入量的基因的更精细定位;和（2）一个新开发的操作性口头MA自我-已经使用该施用方法来验证MADR系作为遗传模型，其显示对MA的增强效应的不同敏感性。这项研究计划将开发一个模型，基因决定的逐步升级，狂欢般的MA摄入量。它还将跟踪定量trat基因座（QTL）定位的结果，该定位确定了小鼠10号染色体上的一个基因座，该基因座占与MA摄入量差异相关的遗传方差的约50%，通过完成更精细的定位和序列分析，这将使识别影响MA成瘾遗传风险的基因和基因网络取得进展。初步数据支持μ阿片受体在这种风险中的重要性，将完成药理学和分子研究，以进一步测试这种机制的重要性。此外，分子分析将探索其他潜在的候选机制，基因敲除小鼠和药物靶点的药理学方法将用于跟踪有希望的机制。有3个具体目标：（1）检查遗传决定的MA摄入模式，升级，暴食样摄入和恢复。对自然奖励强化的敏感性的潜在差异 （2）利用现有的一组间隔特异性同源品系更精细地定位10号染色体QTL;测量这些同源品系中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饮用和相关性状的假设;（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、测序和Western印迹分析;使用这些数据来确定具体机制，应使用敲除和药理学方法测试其对MA摄入量的影响。还将完成MADR系中μ-阿片受体的功能分析，其是10号染色体间隔中的一个候选基因。这项工作有可能开发一个所需的遗传动物模型的高MA摄入量，利用现有的遗传风险，在这个模型的发展。此外，阿片系统参与的研究与正在进行的临床工作很好地吻合，表明接受丁丙诺啡或美沙酮治疗（均为阿片受体激动剂）治疗阿片依赖的个体中MA使用的伴随变化。遗传模型的使用将表明MA使用遗传风险较高的动物是否对阿片类药物和探索的其他药物干预敏感。