NEW METHOD FOR STUDYING DRUG SELF ADMINISTRATION IN MICE

Trans-NIH 小鼠计划目前正在进行中，旨在开发新的、 经济有效的高通量表型技术来评估特定 实验室近交系中中枢神经系统功能的组成部分 老鼠。开发此类技术的目的之一就是将该技术应用于 突变小鼠；期望对复杂性状进行遗传分析 将促进基本的大脑过程和中枢疾病 神经系统将得到更好的理解和治疗。多次击倒小鼠 现在已经存在，但人们对它们的功能意义知之甚少 改变了基因。 Trans-NIH 有许多令人感兴趣的复杂行为 鼠标倡议；其中包括认知、学习和记忆以及获取 以及寻求滥用药物。这项研究的目标是开发一种新的 可在近交系和近交系中长期使用的可卡因自我给药方法 基因敲除小鼠品系可模拟人类的全部行为 或与毒瘾有关的经历。其中包括收购、 寻求毒品和吸毒行为的维持、消除和恢复 行为。本提案旨在开发一种可卡因的方法 自我给药，其中离散剂量的雾化可卡因 在刺鼻响应后间歇性地传送到嗅探端口，因此 避免了以前方法所施加的许多限制。有三个 实现这一目标的具体目标： (1) 设计一种能够 间歇性地可靠地输送离散剂量的雾化可卡因 基础； (2) 开发并验证这种可卡因吸入方法 通过训练小鼠使用鼻柱来对近交系小鼠进行自我给药 可卡因输送并通过改变吸入可卡因的剂量和 获得该信息所需的响应要求； (3)将该方法应用在 通过研究硝酸的影响，研究近交系和基因敲除小鼠品系 氧化物合酶缺乏对获得、维持、消退和 恢复神经元可卡因寻求和可卡因自我给药 NOS 基因敲除小鼠和经过 NOS 抑制剂治疗的近交系小鼠。

The Trans-NIH Mouse Initiative is now underway for developing new, cost-effective, high throughput phenotyping techniques to assess specific components of central nervous system function in inbred strains of laboratory mice. One purpose for developing such techniques is to apply this technology to mutant mice; with the expectation that the genetic analysis of complex traits will be facilitated and that basic brain processes and diseases of the central nervous system will be better understood and treated. Numerous mouse knockouts now exist, but little is known regarding the functional significance of their altered genetics. There are many complex behaviors of interest in the Trans-NIH Mouse Initiative; among them are cognition, learning and memory, and the taking and seeking of drugs of abuse. The goal of this research is to develop a new method of cocaine self-administration that can be used long-term in inbred and genetic knockout strains of mice to simulate the full array of human behaviors or experiences associated with drug addiction. These include the acquisition, maintenance, extinction and reinstatement of drug-seeking and drug-taking behavior. The present proposal seeks to develop a method of cocaine self-administration whereby a discrete dose of aerosolized cocaine is intermittently delivered to a sniff port after a nose-poke response, thus avoiding many of the limitations imposed by previous methods. There are three specific aims to accomplish this goal: (1) Design an apparatus that can reliably deliver a discrete dose of aerosolized cocaine on an intermittent basis; (2) Develop and validate this inhalation method of cocaine self-administration in an inbred mouse strain by training mice to nose pole for cocaine delivery and by varying both the dose of inhaled cocaine and the response requirements necessary for obtaining it; (3) Apply this method in inbred and genetic knockout strains of mice by studying the effects of nitric oxide synthase deficiency on the acquisition, maintenance , extinction and reinstatement of cocaine-seeking and cocaine self-administration in neuronal NOS knockout mice and in inbred strains of mice after NOS inhibitor treatment.