Fine Mapping Genes for Cocaine Locomotor Response in ENU Mutagenized Mice

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）成瘾的脆弱性受遗传和环境因素的影响。遗传因素可能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。应激反应途径中的异常适应也与药物依赖的发展有关，尽管这种关系已经牢固确立，但其潜在的神经生物学机制尚未得到很好的理解。虽然没有动物模型可以复制人类药物滥用综合征的整个谱系，但确实存在某些药物相关行为的动物模型，包括急性运动激活，行为敏化和对药物治疗的条件性位置偏好，以及药物自我给药率。我们已经确定了一个ENU诱导的突变体，高，这表明hypermotorism在一个新的环境中，夸张的运动反应的精神兴奋剂可卡因和哌甲酯和长期释放的皮质酮后，急性应激。我们认为，这些动物表现出的异常压力和药物反应是相关的;我们的假设是，夸大的运动反应，精神兴奋剂是加剧了以前暴露于压力事件。使用单核苷酸多态性（SNP）基因分型，我们已经映射到12号染色体上的一个59兆碱基区域的Highper突变。该区域包含411个基因，其中没有一个先前与药物和应激反应有关。因此，Highper可能代表了一种新的模型，用于研究压力和药物反应行为域之间的关系。在这个提议中，我们概述了一个实验策略，以解决我们的三个主要目标：1）进一步表征Highper线，以更好地了解异常的压力和精神刺激反应以及两者之间的联系2）精细映射和识别致病突变和3）表征由基因突变在体内和体外引起的功能破坏。

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.