QUANTITATIVE DOPAMINE RECEPTOR PHARMACODYNAMICS FROM FMRI

项目描述（由申请人提供）：本项目将实证检验是否可以从功能性磁共振成像（fMRI）中提取药物剂量对脑功能影响的定量信息。我们已经开发了一种方法来确定ED50 -产生最大效果的50%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），已经在模拟数据和非人灵长类动物的初步数据上得到了令人鼓舞的结果。拟议的实验将使用多巴胺激动剂（SKF82958，普拉克索）测试模型。多巴胺是大脑中重要的神经递质，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ED50：多巴胺激动剂对催乳素分泌的影响将以传统的方式（每个剂量的药物独立测量）从血清样本中确定，而脑血流动力学的变化将使用我们新的QPDI方法和fMRI BOLD信号在单个实验中测量。这种方法在科学研究和临床医学中测试大脑对药物的反应具有潜在的广泛应用。公共卫生相关性：我们建议测试一种新的方法，从功能性磁共振成像中获得定量的药效学信息，并在活体大脑中使用特定的药理学药物。该方法可用于疾病的诊断和药物剂量的确定，对研究疾病的生理机制和开发治疗疾病的新药具有重要意义。

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.