NMDA RECEPTOR AS THERAPEUTIC TARGET FOR PARKINSON?S DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目研究的目的是在帕金森病动物模型（6-OH-多巴胺损伤大鼠）中获得NR 2D型NMDA受体阻断剂潜在抗帕金森病作用的体内确认。 这些药物最有可能通过阻断丘脑底核中的NR 2D受体起作用，丘脑底核是帕金森病中过度活跃的结构。 NR 2D受体阻断剂可使该核的活性正常化。 为了验证这一假设，我们设计了三个实验：（1）建立我们最好的NR 2D选择性拮抗剂抑制底丘脑神经元天然含NR 2D的NMDA受体的量效曲线。 这些数据与体内药代动力学数据的组合将使我们能够估计受体结合率作为给药剂量的函数。 (2)我们将使用免疫组织化学在正常大鼠和用6-OH-多巴胺处理的大鼠中确定NR 2D蛋白分布，以确认NR 2D受体存在于帕金森病的动物模型中。 (3)我们将评估选择性阻断基底神经节神经元中含NR 2D受体改变6-OHDA损伤动物运动行为的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the studies in this project is to obtain in vivo confirmation of the potential antiparkinsonian effects of blockade of NR2D-type NMDA receptors in an animal model of Parkinson's disease, the 6-OH-dopamine-lesioned rat. These agents are most likely to work by blocking NR2D receptors in the subthalamic nucleus, a structure which is overactive in Parkinson's disease. NR2D receptor blockade may act to normalize the activity in this nucleus. To test this hypothesis, three experiments are planned: (1) We will establish the concentration-effect curve for inhibition of native NR2D-containing NMDA receptors in subthalamic neurons by our best NR2D-selective antagonist. The combination of these data with in vivo pharmacokinetic data will allow us to estimate receptor occupancy as a function of administered dose. (2) We will determine the NR2D protein distribution using immunohistochemistry in normal rats and rats treated with 6-OH-dopamine to confirm that NR2D receptors are present in this animal model of Parkinson's disease. (3) We will evaluate the ability of selective blockade of NR2D-containing receptors in basal ganglia neurons to alter motor behavior in 6-OHDA-lesioned animals.