Mouse Behavior Models of Cocaine Addiction

简介(申请人提供)：将基因打靶引入 对大脑功能的研究迅速推进了我们对各种不同 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 被用来确定各种基因产物在成瘾中的作用 进程。我们建议开发三个不同的行为模型来应用于 研究药物成瘾，并将这种模型扩展到专门用于 转基因小鼠。我们还提议开始一系列广泛的 研究确定正向遗传方法识别 与可卡因成瘾有关的基因。第一种模式利用了一种新的信号 从计划切换任务，以加强对 加强低速率响应的时间表。FR-8评估行为 而DRL-90评估的是工作记忆、反应抑制和 冲动。第二个模型是评估行为方面的模型 表明从反复的可卡因接触中戒断。我们发现， 连续几天暴饮式服用可卡因不会导致 不仅要对可卡因的运动敏感化挑战，而且要深刻 在可卡因戒除的头几天，夜间活动不足。这个 第三种模式将利用可卡因自我管理与变种的 毒品寻觅行为的消亡/复活模式。除 成功地使用转基因方法来确定基因如何与 特殊功能，正向遗传学的使用(从表型到 基因)也是非常有用的。要使用此方法，您必须拥有 快速高通量筛选感兴趣的突变。我们建议测试一下 使用两个快速高通量筛查作为可能的决定因素的可能性 改变对可卡因敏感性的突变。这些模型的发展 应允许对与吸毒有关的行为进行表型表征 和药物寻找，并为各种转基因小鼠提供新的测试。

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.