Betarbet Ranjita, Greenamyre J Timothy
Department of Neurology and Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA.
Exp Neurol. 2004 Oct;189(2):393-403. doi: 10.1016/j.expneurol.2004.05.041.
In Parkinson's disease (PD), striatal dopamine deficiency has been associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. In this study, we simultaneously analyzed the regulation of D1 and D2 dopamine receptors and levels of the neuropeptides, substance P, and enkephalin (ENK) in various basal ganglia nuclei following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation of striatum in nonhuman primates. Both unilateral and bilateral lesioned animals were used for this study. Striatal dopamine deficiency resulted in distinct alterations in D1, D2, substance P, and enkephalin levels and distribution: (1) Both D1 and D2 protein levels were significantly up-regulated in striatum. (2) There was an overall up-regulation of striatal substance P expression following dopamine denervation. (3) Substance P distribution was 'reversed' in dopamine depleted striatum: striosomes, which normally express higher levels of substance P, showed decreased expression, whereas substance P expression was up-regulated in the matrix. (4) Substance P expression was up-regulated in the internal segment of the globus pallidus (GPi), but remained unchanged in substantia nigra (SN). (5) Enkephalin levels were increased in striatum and the external segment of the globus pallidus (GPe), but not in substantia nigra. All the changes were more pronounced in the bilateral lesioned monkeys, though the data represent a pooled statistical evaluation of unilateral and bilateral lesioned monkeys. Our studies indicate that D1 and D2 dopamine receptors and substance P and enkephalin undergo regulatory changes in response to nigrostriatal dopamine denervation. Simultaneous study of the alterations in these various components of the 'direct' and 'indirect' pathways in the same animals will enable better understanding of the pathophysiology of PD and its therapeutic targets.
在帕金森病（PD）中，纹状体多巴胺缺乏与基底神经节功能和神经化学解剖结构的复杂变化有关。在本研究中，我们在非人灵长类动物中，通过1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导纹状体多巴胺能去神经支配后，同时分析了各种基底神经节核团中D1和D2多巴胺受体的调节以及神经肽P物质和脑啡肽（ENK）的水平。本研究使用了单侧和双侧损伤的动物。纹状体多巴胺缺乏导致D1、D2、P物质和脑啡肽水平及分布出现明显改变：（1）纹状体中D1和D2蛋白水平均显著上调。（2）多巴胺去神经支配后，纹状体P物质表达总体上调。（3）在多巴胺耗竭的纹状体中，P物质分布“反转”：通常表达较高水平P物质的纹状体小体表达降低，而基质中P物质表达上调。（4）苍白球内侧部（GPi）中P物质表达上调，但黑质（SN）中保持不变。（5）纹状体和苍白球外侧部（GPe）中脑啡肽水平升高，但黑质中未升高。所有这些变化在双侧损伤的猴子中更为明显，尽管数据是对单侧和双侧损伤猴子的汇总统计评估。我们的研究表明，D1和D2多巴胺受体以及P物质和脑啡肽会因黑质纹状体多巴胺去神经支配而发生调节性变化。在同一动物中同时研究“直接”和“间接”通路这些不同组分的改变，将有助于更好地理解PD的病理生理学及其治疗靶点。
