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

描述(由申请人提供)：我们建议进行一项多学科的翻译遗传学研究，以确定影响小鼠和人类对兴奋剂药物甲基苯丙胺和苯丙胺敏感性的基因。我们将用小鼠来更好地定义染色体区域(也称为数量性状基因座或QTL)，这些区域包含影响对甲基苯丙胺急性运动刺激效应敏感性的基因。这将使用两种互补的方法来实现：同源品系和先进的杂交品系。使用这些技术，我们将能够以一定的精度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候选基因。我们预计，这份基因清单将包括那些导致小鼠对甲基苯丙胺反应不同的基因。然后，我们将在经过仔细筛选的健康人类志愿者样本中，探索这些基因的多态对苯丙胺主观反应的影响。所有志愿者在参与研究前将给予知情同意。我们将使用双盲受试者内设计，每个受试者在4个疗程中以随机顺序接受一次安非他明(安慰剂，5，10和20毫克)。在服用药物或安慰剂的过程中，受试者将自我报告他们的情绪和认知经历，预计其中包括一种受药物影响的主观感觉，以及不同程度的欣快感和焦虑感。我们还将评估他们在行为任务中的表现，并记录会议过程中的生理数据。然后，我们将研究小鼠研究中所选基因的多态与对苯丙胺的反应之间的关系。我们预计，其中一些基因具有与人类志愿者对苯丙胺的反应相关的多态，并可能导致这些差异。我们认为，对安非他明、甲基苯丙胺和可卡因等刺激性药物的急性反应的差异，对于确定药物滥用的遗传风险非常重要。识别这些基因可能有助于开发治疗或预防药物滥用和成瘾的新治疗策略。

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.