Lee Joohyung, Zhu Wen-Mei, Stanic Davor, Finkelstein David I, Horne Marjorie H, Henderson Jasmine, Lawrence Andrew J, O'Connor Louise, Tomas Doris, Drago John, Horne Malcolm K
Brain Injury and Repair, Howard Florey Institute, University of Melbourne, Parkville,VIC, 3010, Australia.
Brain. 2008 Jun;131(Pt 6):1574-87. doi: 10.1093/brain/awn085. Epub 2008 May 16.
Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of 'wearing off' and dyskinaesia in Parkinson's disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until approximately 60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, L-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by L-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in L-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and 'wearing off'.
储存能力衰竭导致纹状体中多巴胺（DA）呈脉冲式释放，这被用来解释帕金森病中“疗效减退”和运动障碍的出现。在本研究中，我们发现6-羟基多巴胺（6-OHDA）损伤大鼠中存活的DA神经元会发芽重新支配纹状体，并维持终末密度直至约60%的神经元丢失。我们证明DA终末密度与纹状体基线DA浓度（[DA]）相关。对6-OHDA损伤大鼠和灵长类动物的电化学及突触体研究表明，纹状体DA再摄取受损以及内侧前脑束纤维DA释放增加有助于维持纹状体DA水平。在终末密度下降60%或更多的损伤大鼠中，给予左旋多巴（L-DOPA）可显著提高纹状体DA水平。L-DOPA产生的纹状体[DA]与运动障碍程度直接相关，表明运动障碍与纹状体高[DA]有关。虽然发芽和多巴胺摄取转运体功能降低预计会导致L-DOPA诱导的[DA]显著增加，但当多巴胺能纤维去神经支配>60%时，[DA]增加最为明显，这表明其他释放位点，如5-羟色胺能纤维可能也有作用。总之，运动障碍程度与DA终末去神经支配程度及突触外纹状体DA水平成正比。我们提出，DA终末发芽和多巴胺摄取转运体功能降低可防止帕金森症状出现，直至黑质神经元丢失约60%，但也会导致纹状体DA释放失调，从而引发运动障碍和“疗效减退”。
