Imaging Nicotine-induced behavioral sensitization with fMRI

使用功能磁共振成像对尼古丁诱导的行为过敏进行成像

• 批准号: 7795248
• 负责人: JEAN A KING
• 金额: $ 35.47万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795248
• 关键词: AMPA Receptors; Address; Affect; Agonist; Animals; Anterior; Behavioral; Brain; Brain region; Conscious; Data; Devices; Dose; Exposure to; Functional Magnetic Resonance Imaging; Globus Pallidus; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Image; Individual; Knowledge; Magnetic Resonance Spectroscopy; Measures; Monoamine Oxidase Inhibitors; N-Methylaspartate; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Nucleus Accumbens; Parahippocampal Gyrus; Pharmaceutical Preparations; Prefrontal Cortex; Rodent; Role; Signal Transduction; Structure; Techniques; Testing; Time; Translating; Ventral Tegmental Area; Visual Cortex; addiction; awake; behavioral sensitization; blood oxygen level dependent; cingulate gyrus; drug of abuse; improved; innovation; mortality; novel; receptor; relating to nervous system; response; tool; transmission process

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.

描述（由申请人提供）：大脑功能性磁共振成像（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一直很缓慢，因为受试者在成像过程中必须保持不动。我们发明了一种设备，可以让我们在清醒时对啮齿动物进行成像，为随着时间的推移非侵入性地研究大脑功能开辟了新的机会。重复暴露于滥用药物引起运动刺激的进行性增加，称为行为敏化。人们认为，致敏是对包括尼古丁在内的药物成瘾的核心。此次重新提交解决了关于尼古丁致敏的两个潜在重要观察结果。首先，可以用fMRI对其进行成像，从而识别相关的大脑结构。通过在成像过程中对致敏动物给予选定的受体激动剂，可以评价单个神经递质在致敏中的作用。我们的初步数据表明，功能磁共振成像可用于确定在不同的大脑区域的谷氨酸受体的敏化作用。本提案的目的是：1）通过血氧水平依赖性对比度（BOLD）测定，确定对致敏动物给予尼古丁是否会导致腹侧被盖区、丘脑核、前额叶皮质、海马、腹侧苍白球、前扣带回、隔和视觉皮质的神经元活动发生变化; 2）确定尼古丁致敏持续多长时间; 3）确定单胺氧化酶抑制剂与尼古丁联合给药如何改变致敏的持续性; 4）研究谷氨酸在致敏表达中的作用。这一建议在使用fMRI研究致敏性方面具有高度创新性。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死亡率的最大贡献者。