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疾病如何发挥作用的认识。 神经递质、受体和效应器参与基本方面 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以应用于 研究毒瘾并扩展此类模型专门用于 基因改造的老鼠。我们还建议开始一系列广泛的 研究以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颖的信号 从强化高速率响应的计划中切换任务 加强低率响应的时间表。 FR-8 评估行为 DRL-90 评估工作记忆、反应抑制和 冲动。第二个模型评估行为的各个方面 表明从反复接触可卡因中戒断。我们发现 连续几天“暴食式”服用可卡因不会导致 不仅对可卡因挑战的运动敏化，而且对深刻的 戒除可卡因的最初几天夜间活动减少。的 第三种模型将利用可卡因自我给药以及一种变体 寻求毒品行为的灭绝/恢复模型。除了 成功使用转基因方法来确定基因如何与 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 快速高通量筛选感兴趣的突变。我们建议测试 使用两个快速高通量筛选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 应允许对与吸毒相关的行为进行表型表征 寻找药物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.