Imaging Nicotine-induced behavioral sensitization with fMRI

描述(申请人提供)：大脑的功能磁共振成像(FMRI)提高了我们对滥用药物的理解。将这种方法应用于有意识的动物方面进展缓慢，因为受试者在成像过程中必须一动不动。我们发明了一种设备，可以让我们在醒着的时候为啮齿动物成像，这为随着时间的推移非侵入性地研究大脑功能打开了新的机会。反复接触滥用药物会引起运动刺激的渐进性增加，称为行为敏感化。人们认为，敏化是包括尼古丁在内的药物成瘾的核心。这份重新提交的报告涉及关于尼古丁敏化的两个潜在的重要观察结果。首先，它可以用功能磁共振成像，从而识别所涉及的大脑结构。单独的神经递质在致敏中的作用可以通过在成像过程中给致敏动物注射选定的受体激动剂来评估。我们的初步数据表明，功能磁共振成像可以用来确定大脑不同区域对谷氨酸受体的敏化作用。该建议的目的是1)确定尼古丁对致敏动物的作用是否会改变腹侧被盖区、伏隔核、前额皮质、海马体、腹侧苍白球、前扣带回、隔区和视皮质的神经元活动(用血氧水平依赖对比法(BOLD)测量)；2)确定尼古丁敏化持续多久；3)确定单胺氧化酶抑制剂与尼古丁联合应用如何改变敏化的持久性；以及4)研究谷氨酸在致敏表达中的作用。这项提议在使用功能磁共振成像来研究致敏方面具有很高的创新性。一旦开发出来，这项技术可以用来将我们对动物致敏的知识转化为对人类致敏及其与成瘾关系的研究。致敏成像可能为探索治疗尼古丁成瘾的新药理学方法提供一个强大的新工具，尼古丁成瘾是发达国家可预防的死亡率的最大贡献因素。

DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) of the brain has improved our understanding of drugs of abuse. Progress in applying this approach to conscious animals has been slow because subjects must be immobile during imaging. We have invented a device that allows us to image rodents while awake, opening new opportunities to study brain function non-invasively over time. Repeated exposure to drugs of abuse evokes a progressive increase in locomotor stimulation, termed behavioral sensitization. It is thought that sensitization is central to addiction to drugs, including nicotine. This resubmission addresses two potentially important observations about nicotine sensitization. First, it can be imaged with fMRI, allowing identification of the brain structures involved. The role of individual neurotransmitters in sensitization can be evaluated through the administration of selected receptor agonists to sensitized animals during imaging. Our preliminary data indicate that fMRI can be used to determine the role in sensitization to glutamate receptors in various brain regions. The aims of this proposal are 1) to determine if the administration of nicotine to sensitized animals produces alterations in neuronal activity in the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, ventral pallidum, anterior cingulate gyrus, septum and visual cortex as measured by blood oxygen level-dependent contrast (BOLD); 2) to determine how long nicotine sensitization persists; 3) to determine how the administration of monoamine oxidase inhibitors in conjunction with nicotine alters the persistence of sensitization; and 4) to investigate the role of glutamate in the expression of sensitization. This proposal is highly innovative in the use of fMRI to study sensitization. Once developed, this technique could be used to translate our knowledge of sensitization in animals to the study of sensitization in humans and its relation to addiction. The imaging of sensitization may provide a powerful new tool for the exploration of novel pharmacologic approaches to treating nicotine addiction, which is the largest contributor to preventable mortality in the developed world.