Imaging Nicotine-induced behavioral sensitization with fMRI

描述（由申请人提供）：脑功能磁共振成像（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的进展缓慢，因为在成像过程中受试者必须是不动的。我们发明了一种设备，可以让我们在清醒的情况下对啮齿动物进行成像，为长期无创研究大脑功能开辟了新的机会。反复暴露于药物滥用引起运动刺激的进行性增加，称为行为敏感化。人们认为，致敏是对包括尼古丁在内的药物上瘾的核心原因。这次重新提交的报告涉及了两个关于尼古丁致敏的潜在重要观察结果。首先，它可以用功能磁共振成像成像，允许识别相关的大脑结构。单个神经递质在致敏中的作用可以通过在成像过程中对致敏动物施用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在不同的大脑区域对谷氨酸受体敏化的作用。本研究的目的是：1)通过血氧水平依赖对比（BOLD）测定致敏动物的腹侧被盖区、伏隔核、前额叶皮层、海马、腹侧苍白球、前扣带回、中隔和视觉皮层的神经元活动是否会产生改变；2)确定尼古丁致敏持续的时间；3)确定单胺氧化酶抑制剂与尼古丁联合使用如何改变致敏的持久性；4)探讨谷氨酸在致敏表达中的作用。该建议在使用功能磁共振成像研究致敏方面具有高度创新性。一旦发展起来，这项技术可以用来将我们对动物致敏的了解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死亡的最大贡献者。

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.