Non-invasive self administration methodology for mice

描述（由申请人提供）： 滥用成瘾药物给社会带来了巨大的负担，但有关药物渴望途径的许多基本问题仍然知之甚少。目前的药物自我给药的动物模型受到与小动物所需的侵入性程序相关的技术困难的限制，特别是在遗传学上易于处理的小鼠中。在这里，我们描述了一种非侵入性的药物自我管理程序的发展，特别是适用于小鼠。在大卫斯蒂芬斯博士的实验室进行的初步研究表明，可以训练小鼠通过气雾剂喷雾鼻内递送可卡因水溶液进行自我给药。在这里，我们建议复制这些结果，并进一步开发和应用这些方法。具体目标包括： 1.使用我们自己实验室中新构建的行为装置，复制斯蒂芬斯实验室中生成的初始数据。 2.进一步验证自我给药模式的对照：这些对照包括使用相关但不成瘾的物质，如利多卡因和测量可卡因暴露的其他生理相关性。测量将包括确定血清和大脑可卡因水平，以及可卡因暴露后运动和心率刺激的测量。 3.应用此范例于小鼠昼夜节律突变体。这些研究是基于观察到mper 1基因敲除小鼠对可卡因缺乏条件性位置偏爱。我们将研究这些小鼠以及mper 1和3基因敲除，以及其他几个昼夜节律基因的突变体。这些研究应该解决这样一个问题，即这种缺陷是否是可卡因特有的，而不是更普遍的奖励途径中的缺陷。 4.从Neuromice.org隐性行为筛选中筛选出显示初始可卡因反应改变的候选动物。对可卡因反应性的初步筛查显示出大量的“putants”，截至本文撰写时36。这些小鼠甚至在它们被充分表征之前就将提供给科学界。我们将获得这些纯合子品系，并在我们的范例中对其进行测试。

DESCRIPTION (provided by applicant): Abuse of addictive drugs puts an enormous burden on society, yet many basic questions regarding drug craving pathways remain poorly understood. Current animal models of drug-self-administration are limited by technical difficulties associated with the invasive procedures required for small animals, particularly in the genetically tractable mouse. Here we describe the development of a non-invasive procedure for drug self-administration that is particularly suited for use in mouse. Preliminary studies conducted in the laboratory of Dr. David Stephens have shown that mice can be trained to self-administer an aqueous solution of cocaine delivered intranasally via an aerosol spray. Here we propose to replicate these results and further develop and apply these methods. Specific aims include: 1. Replication of the initial data generated in Stephens' laboratory, using newly constructed behavioral apparati in our own laboratory. 2. Controls to further validate the self-administration paradigm: these controls include use of related but nonaddicting substances such as lidocaine and measurement of additional physiological correlates of cocaine exposure. The measurements will include determination of serum and brain cocaine levels, and measurement of locomotor and heart-rate stimulation following cocaine exposure. 3. Application of this paradigm to mouse circadian mutants. These studies are based on the observation that mper 1 knockout mice show a lack of conditioned place preference to cocaine. We will study these mice as well as mper 1 and 3 knockouts, and mutants in several other circadian genes. These studies should address the question of whether the defect is specific to cocaine versus defects in more general reward pathways. 4. Screen candidate animals from the Neuromice.org recessive behavioral screen that show alterations in intitial cocaine responses. Initial screening for cocaine responsiveness is showing a large number of 'putants', 36 as of this writing. These mice will be made available to the scientific community even before they are fully characterized. We will obtain these lines when available as homozygotes and test them in our paradigm.