Imaging Dopamine Mediated Neurovascular Coupling

描述(由申请人提供)：这一竞争更新寻求继续资助我们的研究，以了解与多巴胺能药物相关的MRI信号变化背后的机制。在这项应用中，我们将寻求确定与刺激各种多巴胺受体亚型有关的信号变化的成分。此外，我们将把这些变化与使用微透析技术测定的多巴胺释放的变化以及使用正电子发射断层扫描(PET)和放射自显影技术对多巴胺受体的定量测量相关联。此外，我们还将探讨阻断不同的多巴胺受体亚型对可卡因和苯丙胺等滥用药物引起的血流动力学变化的影响。然后，我们将分析这些受体亚型在两种不同的多巴胺能调制模型中的变化。首先，我们将研究可卡因自我管理带来的变化。因此，我们将对多巴胺受体亚型随可卡因暴露和戒断而发生的变化进行纵向测量。这些变化将通过实时聚合酶链式反应、正电子发射体层成像、核磁共振成像和微透析进行检测。我们还将使用6-OHDA多巴胺模型进行配对研究，以检查多巴胺能耗竭对多巴胺受体亚型的影响，以及它们对可卡因和苯丙胺等药物引起的信号变化的影响。最后，我们将提高我们使用高对比度噪声技术获取数据的定量能力，以及使用多巴胺能释放和再摄取曲线模拟信号变化的能力。

DESCRIPTION (provided by applicant): This competing renewal seeks to continue funding for our studies to understand the mechanisms behind MRI signal changes associated with dopaminergic drugs. In this application we will seek to determine the components of the signal changes that are related to stimulation of the various dopamine receptor sub-types. In addition, we will correlate these changes with changes that are noted in dopamine release as determined using microdialysis techniques and with quantitative measurements of dopamine receptors using positron emission tomography (PET) and autoradiographic techniques. Further, we will probe the effects that blocking different dopamine receptor sub-types will have on the hemodynamic changes elicited by drugs of abuse such as cocaine and amphetamines. Then we will assay how these receptor sub-types change in two different models of dopaminergic modulation. In the first, we will examine changes that are attendant upon cocaine self-administration. Thus, we will perform longitudinal measurements of changes in dopamine receptor sub- types as a function of cocaine exposure and withdrawal. These changes will be assayed using both real time PCR, PET imaging, MRI and microdialysis. We will also perform companion studies using the 6-OHDA dopamine model to examine the effects of dopaminergic depletion on dopamine receptor subtypes, and their effects on signal changes evoked by drugs such as cocaine and amphetamine. Finally, we will improve both our quantitative ability to acquire the data using higher contrast to noise techniques as well as model the signal changes using dopaminergic release and reuptake curves.