Oueslati Abid, Sgambato-Faure Véronique, Melon Christophe, Kachidian Philippe, Gubellini Paolo, Amri Mohammed, Kerkerian-Le Goff Lydia, Salin Pascal
Developmental Biology Institute of Marseille Luminy, Unité Mixte de Recherche 6216, Centre National de la Recherche Scientifique-Université de la Méditerranée, 13402 Marseille cedex 20, France.
J Neurosci. 2007 Feb 28;27(9):2377-86. doi: 10.1523/JNEUROSCI.2949-06.2007.
This study examined the cellular changes produced in the striatum by chronic L-DOPA treatment and prolonged subthalamic nucleus high-frequency stimulation (STN-HFS) applied separately, successively, or in association, in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Only animals showing severe L-DOPA-induced dyskinesias (LIDs) were included, and STN-HFS was applied for 5 d at an intensity efficient for alleviating akinesia without inducing dyskinesias. L-DOPA treatment alone induced FosB/deltaFosB immunoreactivity, exacerbated the postlesional increase in preproenkephalin, reversed the decrease in preprotachykinin, and markedly increased mRNA levels of preprodynorphin and of the glial glutamate transporter GLT1, which were respectively decreased and unaffected by the dopamine lesion. STN-HFS did not affect per se the postlesion changes in any of these markers. However, when applied in association with L-DOPA treatment, it potentiated the positive modulation exerted by L-DOPA on all of the markers examined and tended to exacerbate LIDs. After 5 d of L-DOPA withdrawal, the only persisting drug-induced responses were an elevation in preprodynorphin mRNA levels and in the number of FosB/deltaFosB-immunoreactive neurons. Selective additional increases in these two markers were measured when STN-HFS was applied subsequently to L-DOPA treatment. These data provide the first evidence that STN-HFS exacerbates the responsiveness of striatal cells to L-DOPA medication and suggest that STN-HFS acts specifically through an L-DOPA-modulated signal transduction pathway associated with LIDs in the striatum. They point to striatal cells as a primary site for the complex interactions between these two therapeutic approaches in PD and argue against a direct anti-dyskinetic action of STN-HFS.
本研究在帕金森病（PD）的6-羟基多巴胺损伤大鼠模型中，分别、先后或联合应用慢性左旋多巴治疗和长期丘脑底核高频刺激（STN-HFS），研究其在纹状体中产生的细胞变化。仅纳入表现出严重左旋多巴诱导的异动症（LIDs）的动物，并以有效缓解运动不能且不诱发异动症的强度进行5天的STN-HFS治疗。单独的左旋多巴治疗诱导FosB/δFosB免疫反应性，加剧损伤后前脑啡肽原的增加，逆转前速激肽的减少，并显著增加前强啡肽原和胶质谷氨酸转运体GLT1的mRNA水平，多巴胺损伤分别使它们降低和未受影响。STN-HFS本身并不影响这些标志物中任何一种损伤后的变化。然而，当与左旋多巴治疗联合应用时，它增强了左旋多巴对所有检测标志物的正向调节作用，并倾向于加剧LIDs。在停用左旋多巴5天后，唯一持续存在的药物诱导反应是前强啡肽原mRNA水平升高和FosB/δFosB免疫反应性神经元数量增加。当在左旋多巴治疗后随后应用STN-HFS时，测量到这两种标志物有选择性的额外增加。这些数据首次证明STN-HFS会加剧纹状体细胞对左旋多巴药物治疗的反应性，并表明STN-HFS通过与纹状体中LIDs相关的左旋多巴调节信号转导途径特异性发挥作用。它们指出纹状体细胞是PD中这两种治疗方法之间复杂相互作用的主要部位，并反对STN-HFS具有直接抗异动症作用的观点。
