Integrative genetic analysis of methamphetamine's motivational effects in mice

描述(由申请人提供)：毒品的主观积极影响被认为是导致药物滥用的早期阶段。药物滥用和最初对药物的积极反应在人类中都是不同的，而且已知有遗传因素。流行病学研究证实，报告对毒品有积极体验的人患上毒瘾的风险更高。因此，我们和其他人认为，对药物的主观积极反应，或“喜欢药物”，代表了药物滥用的一种中间表型。老鼠是研究哺乳动物大脑和行为遗传基础的有力工具。我们将使用条件性位置偏好(CPP)范式来评估甲基苯丙胺(MA)在小鼠身上的动机特性，在CPP范式中，MA和生理盐水在几天的时间内交替与不同的环境配对。在最后一天，小鼠被允许探索这两种环境，对MA的偏好是通过在药物配对环境中花费的时间来衡量的。CPP被广泛用于研究药物对啮齿动物的奖赏效应，最近在一项健康人体研究中得到了证实。重要的是，自我报告的对药物配对房间的偏好与人类自我报告的精神刺激剂的愉悦效果相关。这表明，除了奖励的其他重要方面，如激励性突出(药物渴求)和学习，CPP还可以用来衡量奖励药物的享乐属性。我们提出了一个强大的系统遗传学分析的CPP在一个先进的交叉品系(AIL)的小鼠。RAIL是由两个自交系杂交多个世代产生的，与传统的遗传杂交相比，它为定位影响数量性状(QTL)的基因座提供了更高的精度。我们将使用一种尖端的测序基因分型(GBS)策略来获得1,000个个体的QTL图谱的基因类型。在这些小鼠的一个子组中，我们还将测量对药物奖励至关重要的三个大脑区域的基因表达。表达数据将使用RNA测序(RNAseq)产生；这些数据将使我们能够识别调节基因表达的QTL(EQTL)。整合基因、表型和基因表达数据是一种有效的方法，它将加快识别导致QTL的基因的进程，并提供对影响药物奖赏效应的生物学机制的洞察。重要的是，拟议的研究提供了在行为科学、复杂特征遗传学、统计学和生物信息学方面进行培训的机会。

DESCRIPTION (provided by applicant): The subjectively positive effects of drugs are thought to contribute to early stages of drug abuse. Both drug abuse and the initially positive response to drugs are variable in humans and are known to have a genetic component. Epidemiological studies have established that individuals who report having a positive experience with drugs are at increased risk to develop drug addiction. Accordingly, we and others have suggested that the subjectively positive response to drugs, or 'drug liking' represents an intermediate phenotype for drug abuse. Mice are powerful tools for studying the mammalian brain and the genetic basis of behavior. We will assess the motivational properties of methamphetamine (MA) in mice using the conditioned place preference (CPP) paradigm in which MA and saline are alternately paired with separate environments over a period of several days. On the last day the mouse is allowed to explore both environments, and preference for MA is measured as the amount of time spent in the drug-paired setting. CPP is widely used to study the rewarding effects of drugs in rodents and was recently demonstrated in a study of healthy human subjects. Importantly, self-reported preference for a drug-paired room is correlated with the self-reported pleasant effects of psychostimulants in humans. This suggests that in addition to other important aspects of reward such as incentive salience (drug wanting) and learning, CPP can be used to measure the hedonic properties of a rewarding drug. We propose a powerful systems genetics analysis of CPP in an advanced intercross line (AIL) of mice. AILs are generated by crossing two inbred strains for multiple generations and offer greater precision for mapping loci that influence quantitative traits (QTLs) than traditional genetic crosses. We will use a cutting- edge genotyping-by-sequencing (GBS) strategy to obtain genotypes for QTL mapping in 1,000 individuals. In a subset of these mice we will also measure gene expression in three brain regions critical to drug reward. Expression data will be generated using RNA-sequencing (RNAseq); those data will allow us to identify QTLs that regulate gene expression (eQTLs). Integrating genotype, phenotype and gene expression data is a powerful approach that will accelerate the process of identifying the genes that cause QTLs and provide insight into the biological mechanisms influencing the rewarding effects of drugs. Importantly, the proposed research provides opportunities for training in behavioral science, complex trait genetics, statistics and bioinformatics.