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全球问题，带来了许多负面的个人和社会后果。对甲基苯丙胺的成瘾（MA）会损害大脑，会诱发精神病，并与犯罪和侵略性增加有关。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以解决其药物滥用问题的关键人口。缺乏用于调查MA使用风险的遗传动物模型和构成风险和使用升级使用的机制。该应用描述了针对人类甲基苯丙胺（MA）使用的遗传小鼠模型的研究，以及鉴定遗传因素和影响MA滥用遗传风险的特定机制。要使用的是（1）由小鼠选择性繁殖的小鼠组成的独特遗传工具（MADR线）和间隔特定的特定异基菌株，用于对影响MA摄入的基因进行细微的映射； （2）一种新开发的操作者口服MA自我管理方法，该方法已被用来验证MADR线作为一种遗传模型，该模型显示出对MA增强作用的差异敏感性。该研究计划将开发出遗传确定的升级，类似暴饮暴食的MA摄入模型。它还将跟进定量TRAT基因座（QTL）映射的结果，该映射确定了小鼠染色体10上的一个基因座，该基因座通过完成更精细的映射和序列分析，占与差异MA摄入相关的遗传方差的约50％，这将允许在识别影响MA添加遗传风险的基因和基因网络中取得进展。初步数据支持MU-阿片受体在这种风险中的重要性，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和敲除小鼠以及可药物靶标的药理学方法，用于后续有希望的机制。有3个特定的目的：（1）检查MA摄入，升级，暴饮暴食的遗传学模式，狂暴的摄入量和恢复原状。通过自然奖励增强敏感性的潜在差异 还将作为此目标的一部分进行检查； （2）使用现有的间隔特定的先天性菌株来更细微地绘制10 QTL染色体；测量这些友善的基因相关性状，以检验以下假设：小鼠染色体10上的共同遗传区域会影响MA饮用和相关性状。 （3）对可能影响MA饮用的基因进行精细绘制染色体QTL的精细映射后，进行了完整的QPCR，序列和蛋白质印迹分析；使用这些数据来识别应使用基因敲除和药理学方法对其对MA摄入的影响进行测试的特定机制。也将完成MADR线中的Mu opioet受体的功能分析，这是10个间隔中的一个候选基因。这项工作具有开发高MA摄入量所需的遗传动物模型，该模型在该模型的发展中利用现有的遗传风险。此外，对阿片类药物系统参与的研究非常吻合，这表明接受丁丙诺啡或美沙酮治疗的个体中的MA使用变化（均为阿片类药物受体激动剂），以伴随着鸦片依赖性。遗传模型的使用将表明使用较高的MA使用遗传风险的动物是否易受阿片类药物和其他探讨的药理干预措施的影响。