Imaging Dopamine Mediated Neurovascular Coupling

描述（由申请人提供）：本次竞争性更新旨在继续为我们的研究提供资金，以了解与多巴胺能药物相关的MRI信号变化背后的机制。在本申请中，我们将寻求确定与各种多巴胺受体亚型的刺激相关的信号变化的组分。此外，我们将这些变化与多巴胺释放的变化相关联，这些变化是使用微透析技术测定的，并使用正电子发射断层扫描（PET）和放射自显影技术定量测量多巴胺受体。此外，我们将探讨阻断不同多巴胺受体亚型对滥用药物（如可卡因和安非他明）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如何在两种不同的多巴胺能调节模型中变化。首先，我们将研究可卡因自我管理后随之而来的变化。因此，我们将对多巴胺受体亚型的变化进行纵向测量，作为可卡因暴露和戒断的函数。将使用真实的时间PCR、PET成像、MRI和微透析来分析这些变化。我们还将使用6-OHDA多巴胺模型进行伴随研究，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安非他明等药物引起的信号变化的影响。最后，我们将提高我们的定量能力，使用更高的对比度噪声技术获取数据，以及使用多巴胺能释放和再摄取曲线模拟信号变化。

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.