QUANTITATIVE DOPAMINE RECEPTOR PHARMACODYNAMICS FROM FMRI

描述（由申请人提供）：本项目将根据经验测试是否可以从功能性磁共振成像（fMRI）中提取有关药物剂量对脑功能影响的定量信息。我们已经开发出一种方法来确定ED 50-产生50%的最大效果所需的药物剂量-从fMRI血氧水平依赖（BOLD）成像获得的数据。这种方法，定量药效学成像（QPDI），已经过测试，模拟数据，并从非人灵长类动物的初步数据令人鼓舞的结果。拟定实验将使用多巴胺激动剂（SKF 82958，普拉克索）测试模型。多巴胺是大脑中一种重要的神经递质，多巴胺能通路与运动障碍、精神疾病和药物滥用有关。我们将测量大脑对药物的两种反应的ED 50：多巴胺激动剂对催乳素分泌的影响将以传统方式从血清样品中确定（对每种剂量的药物进行独立测量），而脑血流动力学的变化将使用我们新的QPDI方法和fMRI BOLD信号在单一实验中测量。该方法具有潜在的广泛应用，用于测试大脑对用于科学研究和临床医学的药理学试剂的反应。公共卫生相关性：我们建议测试一种新的方法，用于获得定量药效学信息的功能磁共振成像与特定的药理剂在一个活的大脑。该方法可用于疾病的诊断和药物剂量的确定，对研究生理机制和开发治疗疾病的新药具有重要价值。

DESCRIPTION (provided by applicant): This project will empirically test whether quantitative information about drug dose effects on brain function can be extracted from functional Magnetic Resonance Imaging (fMRI). We have developed a method for determining the ED50 - the drug dose required to produce 50 percent of the maximum effect - from data acquired from fMRI blood oxygen level dependent (BOLD) imaging. This method, quantitative pharmacodynamic imaging (QPDI), has been tested with encouraging results on simulated data, and on preliminary data from nonhuman primates. The proposed experiments will test the model with dopamine agonists (SKF82958, pramipexole). Dopamine is a critical neurotransmitter in the brain, and dopaminergic pathways are associated with movement disorders, mental illness and drug abuse. We will measure ED50 for two responses of the brain to the drugs: the effect of dopamine agonists on prolactin secretion will be determined from blood serum samples in the traditional manner (independent measurements for each dose of drug), while changes in brain hemodynamics will be measured in a single experiment using our new QPDI method and fMRI BOLD signal. This method has potentially wide application for testing the brain's response to pharmacological agents for use in scientific research and clinical medicine. PUBLIC HEALTH RELEVANCE: We propose to test a new method for obtaining quantitative pharmacodynamic information from functional magnetic resonance imaging with specific pharmacological agents in a living brain. This method could be used to diagnosis disorders and determine appropriate drug dosage, and could be invaluable for researching physiological mechanisms and developing new drugs for treating diseases.