Integrative genetic analysis of methamphetamine's motivational effects in mice

描述（由申请人提供）：药物的主观积极作用被认为有助于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是可变的，并且已知具有遗传成分。流行病学研究已经确定，报告对毒品有积极体验的个人发展成吸毒成瘾的风险增加。因此，我们和其他人认为，主观上对药物的积极反应，或“药物喜好”代表了药物滥用的中间表型。 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）范式评估甲基苯丙胺（MA）在小鼠中的动机特性，在该范式中，MA和生理盐水在几天的时间内交替配对与单独的环境。在最后一天，允许小鼠探索两种环境，并且测量对MA的偏好作为在药物配对设置中花费的时间量。CPP被广泛用于研究药物对啮齿动物的奖励作用，最近在健康人类受试者的研究中得到了证实。重要的是，自我报告的对药物配对房间的偏好与自我报告的人类精神兴奋剂的愉快效果相关。这表明，除了奖励的其他重要方面，如激励显着性（药物需求）和学习，CPP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CPP在先进的互交系（AIL）的小鼠。AILs是通过将两个近交系杂交多代而产生的，并且与传统的遗传杂交相比，AILs为定位影响数量性状（QTL）的基因座提供了更高的精度。我们将使用最先进的测序基因分型（GBS）策略获得1,000个个体的QTL作图基因型。在这些小鼠的一个子集中，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）生成;这些数据将使我们能够识别调控基因表达的QTL（eQTL）。整合基因型、表型和基因表达数据是一种强有力的方法，它将加速鉴定导致QTL的基因的过程，并提供对影响药物奖赏效应的生物学机制的深入了解。重要的是，拟议中的研究为行为科学、复杂性状遗传学、统计学和生物信息学提供了培训机会。

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.