NMDA RECEPTOR AS THERAPEUTIC TARGET FOR PARKINSON?S DISEASE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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。 将该数据与体内药代动力学数据相结合，将使我们能够估计受体结合率作为给药剂量的函数。 (2)采用免疫组织化学法测定正常大鼠和6-OH-多巴胺处理大鼠的NR 2D蛋白分布，以证实NR 2D受体存在于该帕金森病动物模型中。 (3)评价选择性阻断基底节神经元中含NR 2D受体改变6-OHDA损伤动物运动行为的能力。 这一项目已经完成，正在准备出版成果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 were planned: (1) To 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 this data with in vivo pharmacokinetic data will allow us to estimate receptor occupancy as a function of administered dose. (2) To 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) To evaluate the ability of selective blockade of NR2D-containing receptors in basal ganglia neurons to alter motor behavior in 6-OHDA-lesioned animals. This project was completed and publications of results are in preparation.