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研究，以识别小鼠和人类中对刺激性药物甲基苯丙胺和苯丙胺的敏感性的基因。我们将使用小鼠更好地定义染色体区域（也称为定量性状基因座或QTL），该染色体区域包含对甲基苯丙胺的急性运动刺激作用影响敏感性的基因。这将使用两种免费方法来实现：先天性菌株和高级跨线。使用这些技术，我们将能够以一定的精度确定影响该性状的基因的位置。然后，我们将使用各种实验和生物信息学方法在这些区域中的基因中解析，这将使我们能够识别出少量的高概率候选基因。我们预计该基因清单将包括负责小鼠甲基苯丙胺反应差异的基因。然后，我们将探讨这些基因中多态性对苯丙胺对苯丙胺的主观反应的影响。所有志愿者将在参与研究之前给予知情同意。我们将使用双盲内部设计的设计，其中每个受试者在4个会话中以随机顺序接收苯丙胺的每个剂量（安慰剂，5,10和20 mg）。在施用药物或安慰剂的会议期间，受试者将自我报告自己的情感和认知经历，预计将包括一种主观的感觉，即受到药物影响，以及不同程度的欣快感和焦虑和焦虑和焦虑。我们还将评估他们在行为任务上的表现，并在会议过程中记录生理数据。然后，我们将检查小鼠研究中选择的基因中对苯丙胺的反应与多态性的反应之间的关系。我们期望某些基因具有与人类志愿者中对苯丙胺反应的差异相关的多态性。我们认为，急性反应对苯丙胺，甲基苯丙胺和可卡因等刺激药物的差异对于确定滥用药物滥用的遗传风险很重要。鉴定这些基因可能有助于制定新的治疗策略来治疗或预防药物滥用和成瘾。