EXTRASTRIATAL FUNCTIONS OF DOPAMINE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 帕金森病的发病原因是黑质致密部多巴胺能神经元变性，导致苍白球外、内节和丘脑底核(STN)神经元活动异常。虽然这些病理活动模式的发展被解释为纹状体多巴胺丢失的结果，由于黑质纹状体束的退化，最近的研究表明纹状体外的多巴胺丢失也可能起到重要作用。 我们的研究正在研究这个问题，重点是向灵长类STN供应多巴胺。我们已经开始分析多巴胺能神经支配的程度，并对11只恒河猴的正常和MPTP治疗的帕金森病猴的STN内多巴胺受体的超微结构定位进行了表征。我们发现MPTP处理降低了STN内多巴胺能纤维的密度。 正在进行的研究使用电子显微镜表征了STN中多巴胺受体的解剖分布和密度。我们还研究了多巴胺受体配体对STN电生理活性的影响。在一只正常动物身上的研究已经完成。目前正在对这种动物进行MPTP治疗状态的研究。 对啮齿动物的研究表明，激活突触前和突触后的多巴胺受体可以增加神经元的放电，减少突触的爆发。这两种作用都被认为是抗帕金森病，提示多巴胺受体激动剂可能在STN中发挥一些有益的抗帕金森病作用。

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. Parkinsonism arises from degeneration of dopaminergic neurons in the substantia nigra pars compacta and resulting abnormal neuronal activity patterns in the external and internal pallidal segments and in the subthalamic nucleus (STN). While the development of these pathologic activity patterns has been explained as the result of striatal dopamine loss, due to degeneration of the nigrostriatal tract, recent studies demonstrate that extrastriatal dopamine loss may also play a significant role. Our studies are examining this issue, focusing on the dopamine supply to the primate STN. We have started to analyze the extent of the dopaminergic innervation and characterize the ultrastructural localization of dopamine receptors within STN of normal and MPTP-treated parkinsonian monkeys in 11 Rhesus monkeys. We found that MPTP-treatment reduces the density of dopaminergic fibers in the STN. Ongoing studies characterize the anatomical distribution and density of dopamine receptors in the STN, using electron microscopy. We have also carried out studies of the effects of dopamine receptor ligands on the electrophysiologic STN activity. Studies in one normal animal were completed. This animals is currently being studied in the MPTP-treated state. Studies in rodents have suggested that activation of pre- and postsynaptic dopamine receptors in the STN increases neuronal firing and reduces bursting. Both actions would be considered antiparkinsonian, suggesting that dopamine receptor agonists may exert some of their beneficial antiparkinsonian effects in STN.