Mouse Behavior Models of Cocaine Addiction

描述（由申请人提供）：将基因靶向引入 对大脑功能的研究迅速提高了我们对各种 神经递质、受体和效应器参与了 大脑功能然而，很少有复杂的行为模型可以 用于确定各种基因产物在成瘾中的作用 过程我们建议开发三种不同的行为模型来应用于 研究药物成瘾，并将这种模型专门用于 转基因老鼠我们还建议开始一系列广泛的 研究确定正向遗传方法的可行性， 与可卡因成瘾有关的基因第一个模型利用了一种新的信号 从强化高速率响应的时间表切换任务， 时间表，以加强低速率响应。一个FR-8评估行为 激活，而DRL-90评估工作记忆，反应抑制和 冲动第二个模型是评估行为的各个方面 表明是因为反复接触可卡因而戒断的我们发现 连续几天“暴食式”服用可卡因 可卡因激发后的运动致敏，但也有深刻的 在可卡因戒断的头几天夜间活动减少。的 第三种模式将利用可卡因自我给药， 寻求毒品行为的消退/恢复模型。除了有 转基因方法的成功使用，以确定基因是如何与 特定功能，使用正向遗传学（从表型到 基因）也非常有用。要使用这种方法，必须有一个 快速高通量筛选目的突变。我们建议测试 使用两个快速高通量筛选作为可能决定因素的可能性 基因突变改变了对可卡因的敏感性这些模型的发展 应该允许与吸毒相关的行为的表型特征 为各种转基因小鼠提供了新的检测手段。

DESCRIPTION (provided by applicant): The introduction of gene targeting to the study of brain function has rapidly advanced our knowledge of how various neurotransmitters, receptors and effectors are involved in basic aspects of brain function. However, there are few sophisticated behavioral models that can be used to establish the roles of various gene products in the addiction process. We propose to develop three distinct behavior models to apply to the study of drug addiction and to extend such models specifically for use in genetically altered mice. We also propose to begin an extensive series of studies to determine the feasibility of forward genetic approaches to identify genes involved in cocaine addiction. The first model utilizes a novel signaled switching task from a schedule that reinforces high-rate responding to a schedule that reinforces low-rate responding. An FR-8 evaluates behavioral activation whereas the DRL-90 evaluates working memory, response inhibition and impulsivity. The second model is one that assesses aspects of behavior indicative of withdrawal from repeated cocaine exposure. We have found that "binge-type" administration of cocaine for several consecutive days leads not only to locomotor sensitization upon cocaine challenge, but also to profound nocturnal hypoactivity during the first several days of cocaine abstinence. The third model will utilize cocaine self-administration coupled to a variant of the extinction/reinstatement model of drug seeking behavior. In addition to the successful use of transgenic approaches to identify how genes are related to particular functions, the use of forward genetics (proceeding from phenotype to gene) has also been tremendously useful. To use this approach one must have a rapid high throughput screen for mutations of interest. We propose to test the possibility of using two rapid high throughput screens as possible determinants of mutations altering sensitivity to cocaine. The development of these models should allow phenotypic characterization of behaviors related to drug taking and drug seeking and provide novel tests for various transgenic mice.