LOSS OF STRIATAL AFFERENTS

特发性帕金森病（PD）是一种进行性神经退行性疾病， 这种疾病折磨着60岁以上人口的1-2%。 PD 由中脑多巴胺（DA）神经元的过早丧失引起， 用药物替代前脑DA作用进行治疗 DA突触 早期PD症状，当75-80%的DA神经元 已经丢失，很容易治疗;疾病的进展是 并发对DA模拟物的稳定和可预测应答丧失 治疗 本提案中概述的实验将利用大鼠模型， 临床前偏侧帕金森症，并将探索适应性突触过程 其试图维持正常的细胞外液（e.c.f.）DA水平 在基底神经节在本供资期间， 同时定量活性的区域性脑微透析 在清醒的动物中进行监测和原位杂交， 开发 这些技术将用于解决以下问题 问题：1）D2 DA自身受体和NMDA的作用是什么？ 谷氨酸受体控制多巴胺的合成和释放速率 幸存的DA终端？2)是DA的D2自身受体控制减少 与D2受体mRNA合成减少相关的突触活动 存活的中脑DA神经元？3)药物独立性是否 DA丢失后的突触后D1和D2受体来源于 D2受体在D1神经元中合成，反之亦然？（4）什么是 间歇性黑质的突触后果相比， 连续DA替代？

Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disease which afflicts 1-2% of the population over 60 years of age. PD arises from premature loss of midbrain dopamine (DA) neurons and is treated symptomatically with drugs which replace DA actions at forebrain DA synapses. Early PD symptoms, which appear when 75-80% of DA neurons have been lost, are easily treated; progression of the disease is complicated by loss of stable and predictable responses to DA-mimetic therapies. The experiments outlined in this proposal will utilize the rat model of preclinical hemiparkinsonism and will explore adaptive synaptic processes which attempt to maintain normal extracellular fluid (e.c.f.) DA levels in basal ganglia. During the current funding period, the techniques of regional brain microdialysis with simultaneous quantitative activity monitoring in awake animals and in situ hybridization have been developed. These techniques will be utilized to address the following questions: 1) What are the roles of D2 DA autoreceptors and NMDA glutamate receptors in controlling DA synthesis and release rates in surviving DA terminals?; 2) Is decreased D2 autoreceptor control of DA synaptic activity associated with decreased synthesis of D2 receptor mRNA in surviving midbrain DA neurons?; 3) Does pharmacologic independence of postsynaptic D1 and D2 receptors after DA loss derive from appearance of D2 receptor synthesis in D1 neurons, and vice-versa?; and 4) What are the synaptic consequences in substantia nigra of intermittent compared to continuous DA replacement?