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 困扰1-2%60岁以上人口的疾病。PD 由于中脑多巴胺(DA)神经元的过早丧失而引起 用替代前脑DA作用的药物对症治疗 DA突触。早期帕金森病症状，当75-80%的DA神经元出现时 已经丢失，很容易治疗；疾病的进展是 对DA模拟物失去稳定和可预测的反应而变得复杂 治疗。 本提案中概述的实验将利用大鼠模型 临床前偏侧帕金森综合征并将探索适应性突触过程 它们试图维持正常的细胞外液(E.C.F.)DA水平 在基底节。在本资助期内， 同时进行定量活动的局部脑微透析 清醒动物的监测和原位杂交已经被 发展起来的。这些技术将用于解决以下问题 问题：1)D2DA自身受体和NMDA的作用是什么 谷氨酸受体在控制多巴胺合成和释放速率中的作用 存活的DA终末？；2)DA的D2自身受体控制减少 突触活性与D2受体mRNA合成减少有关 在存活的中脑DA神经元中？；3)药物独立性 多巴胺丢失后突触后D1和D2受体的出现 D2受体在D1神经元中的合成，反之亦然？以及4)什么是 间歇性大鼠黑质突触后果的比较 不断更换DA？

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?