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Systems Genetic Analysis of Methamphetamine's Motivational Effects in a Mouse AIL

甲基苯丙胺对小鼠 AIL 的激励作用的系统遗传学分析

基本信息

批准号：
9195288
负责人：
ABRAHAM A PALMER
金额：
$ 8.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195288
关键词：
Systems Genetic Analysis Methamphetamine Motivational

项目摘要

DESCRIPTION (provided by applicant): We propose a multidisciplinary, translational genetic study to identify genes that influence sensitivity to the stimulant drugs methamphetamine and amphetamine in mice and humans. We will use mice to better define chromosomal regions (also called quantitative trait loci or QTL) that contain genes that influence sensitivity to the acute locomotor stimulant effects of methamphetamine. This will be accomplished using two complimentary approaches: congenic strains, and advanced intercross lines. Using these techniques, we will be able to determine, with some precision, the location of genes that influence this trait. We will then use a variety of experimental and bioinformatic approaches to parse among the genes located in those regions, which will allow us to identify a small number of high probability candidate genes. We expect that this list of genes will include those responsible for differences in the response to methamphetamine in the mice. We will then explore the effect of polymorphisms in these genes on the subjective response to amphetamine in a sample of carefully screened, healthy human volunteers. All volunteers will give informed consent prior to participation in the study. We will use a double-blind, within-subject design in which each subject receives each dose (placebo, 5,10 and 20 mg) of amphetamine once, in a randomized order, over the course of 4 sessions. During the sessions when drug or placebo has been administered, subjects will self-report their emotional and cognitive experiences, which are expected to include a subjective feeling of being under the influence of a drug, as well as varying degrees of euphoria and anxiety. We will also evaluate their performance on behavioral tasks, and record physiological data over the course of the sessions. We will then examine the relationship between the response to amphetamine and polymorphisms in the genes selected in the mouse studies. We expect that some of the genes have polymorphisms that are associated with, and may cause, differences in the response to amphetamine among the human volunteers. We believe that differences in the acute response to stimulant drugs like amphetamine, methamphetamine and cocaine are important for determining the genetic risk for the development of drug abuse. Identification of these genes may be useful for developing new therapeutic strategies to treat or prevent drug abuse and addiction.

描述（由申请人提供）：我们提出了一项多学科的转化遗传学研究，以确定影响小鼠和人类对兴奋剂甲基苯丙胺和安非他明敏感性的基因。我们将使用小鼠来更好地定义染色体区域（也称为数量性状位点或QTL），这些区域包含影响对甲基苯丙胺急性运动刺激作用敏感性的基因。这将通过两种互补的方法来完成：同源菌株和先进的交叉系。利用这些技术，我们将能够精确地确定影响这一特征的基因的位置。然后，我们将使用各种实验和生物信息学方法来解析位于这些区域的基因，这将使我们能够识别少量高概率的候选基因。我们期望这个基因列表将包括那些负责小鼠对甲基苯丙胺反应差异的基因。然后，我们将在精心筛选的健康人类志愿者样本中探索这些基因多态性对安非他明主观反应的影响。所有志愿者在参与研究前都将给予知情同意。我们将采用双盲、受试者内设计，在4个疗程中，每个受试者按随机顺序接受一次安非他明的每种剂量（安慰剂、5、10和20毫克）。在服用药物或安慰剂期间，受试者将自我报告他们的情绪和认知体验，其中预计包括受药物影响的主观感觉，以及不同程度的欣快感和焦虑。我们还将评估他们在行为任务上的表现，并记录整个过程中的生理数据。然后，我们将检查对安非他明的反应与小鼠研究中选择的基因多态性之间的关系。我们预计，其中一些基因具有多态性，这与人类志愿者对安非他命的反应差异有关，并可能导致这种差异。我们认为，对安非他明、甲基苯丙胺和可卡因等兴奋剂的急性反应的差异对于确定药物滥用发展的遗传风险是重要的。鉴定这些基因可能有助于开发新的治疗策略来治疗或预防药物滥用和成瘾。