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Fine Mapping Genes for Cocaine Locomotor Response in ENU Mutagenized Mice

ENU 诱变小鼠可卡因运动反应基因的精细定位

基本信息

批准号：
7847679
负责人：
Lisa M Tarantino
金额：
$ 17.51万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847679
关键词：
Acute Address Alcohols Amphetamines Animal Model Animals Behavior Behavioral Bioinformatics Breeding Candidate Disease Gene Chromosome Mapping Chromosomes, Human, Pair 12 Cloning Cocaine Corticosterone Development Disease Drug Addiction Drug abuse Environment Environmental Risk Factor Ethylnitrosourea Exhibits Exposure to Gene Mutation Genes Genetic Genomics Genotype Goals Human In Vitro Induced Mutation Link Maps Methylphenidate Molecular Mus Mutation Pathway interactions Pharmaceutical Preparations Phenotype Physiological Recombinants Research Personnel Self Administration Single Nucleotide Polymorphism Site Stress Stressful Event Study models Syndrome Transgenic Organisms addiction behavioral sensitization biological adaptation to stress drug of abuse gene function in vivo insight mutant neurobiological mechanism novel preference programs psychostimulant research study response stressor

项目摘要

DESCRIPTION (provided by applicant): Vulnerability to develop addiction to psychostimulants, including cocaine and amphetamine, as well as other drugs, like alcohol, is influenced by both genetic and environmental factors. Genetic factors may modulate differing initial responses to drugs of abuse in humans and this has been linked to the propensity to develop a drug abuse disorder. Abnormal adaptations in stress response pathways have also been implicated in the development of drug dependence and while this relationship is firmly established, the underlying neurobiological mechanisms are not well understood. While no animal model exists that reproduces the entire spectrum of the drug abuse syndrome in humans, animal models do exist for certain drug-related behaviors including acute locomotor activation, behavioral sensitization and conditioned place preference in response to drug treatment, as well as rates of drug self-administration. We have identified an ENU-induced mutant, Highper, that shows hyperlocomotion in a novel environment, an exaggerated locomotor response to the psychostimulants cocaine and methylphenidate and a prolonged release of corticosterone following an acute stressor. We believe that the abnormal stress and drug responses exhibited by these animals are related; our hypothesis is that the exaggerated locomotor response to psychostimulants is exacerbated by previous exposure to stressful events. Using single nucleotide polymorphism (SNP) genotyping, we have mapped the Highper mutation to a 59 megabase region on chromosome 12. This region contains 411 genes, none of which has previously been implicated in both drug and stress responses. Thus, Highper may represent a novel model for studying the relationship between the stress and drug response behavioral domains. In this proposal, we outline an experimental strategy to address our three primary goals: 1) to further characterize the Highper line to better understand the abnormal stress and psychostimulant responses and the link between the two 2) to fine map and identify the causative mutation and 3) to characterize the functional disruption caused by the gene mutation both in vivo and in vitro.

描述（由申请人提供）：对精神兴奋剂（包括可卡因和安非他明）以及其他药物（如酒精）产生成瘾的脆弱性受到遗传和环境因素的影响。遗传因素可能会调节人类对滥用药物的不同初始反应，这与发展药物滥用障碍的倾向有关。应激反应途径的异常适应也与药物依赖的发展有关，虽然这种关系已牢固确立，但潜在的神经生物学机制尚不清楚。虽然不存在能够重现人类全部药物滥用综合症的动物模型，但确实存在某些与药物相关的行为的动物模型，包括急性运动激活、行为敏化和对药物治疗的反应的条件性位置偏好，以及药物自我给药率。我们发现了一种 ENU 诱导的突变体 Highper，它在新的环境中表现出过度运动，对精神兴奋剂可卡因和哌醋甲酯的过度运动反应，以及在急性应激源后皮质酮的长时间释放。我们认为这些动物表现出的异常应激和药物反应是相关的；我们的假设是，对精神兴奋剂的过度运动反应因之前接触过压力事件而加剧。利用单核苷酸多态性 (SNP) 基因分型，我们将 Highper 突变定位到 12 号染色体上的 59 兆碱基区域。该区域包含 411 个基因，其中没有一个基因与药物和应激反应有关。因此，Highper 可能代表了一种研究压力和药物反应行为领域之间关系的新模型。在本提案中，我们概述了一个实验策略来实现我们的三个主要目标：1）进一步表征 Highper 系列，以更好地了解异常压力和精神刺激反应以及两者之间的联系 2）精细绘制并识别致病突变 3）表征体内和体外基因突变引起的功能破坏。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of QTL for locomotor activation and anxiety using closely-related inbred strains.

使用密切相关的近交系鉴定运动激活和焦虑的 QTL。

DOI：
发表时间：
2008
期刊：
Genes, brain, and behavior
影响因子：
0
作者：
Bailey,JaniceS;Grabowski-Boase,Laura;Steffy,BrianM;Wiltshire,Tim;Churchill,GaryA;Tarantino,LisaM
通讯作者：
Tarantino,LisaM

Forward genetic approaches to understanding complex behaviors.