Picconi Barbara, Paillé Vincent, Ghiglieri Veronica, Bagetta Vincenza, Barone Ilaria, Lindgren Hanna S, Bernardi Giorgio, Angela Cenci M, Calabresi Paolo
Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS c/o CERC, Rome, Italy.
Neurobiol Dis. 2008 Feb;29(2):327-35. doi: 10.1016/j.nbd.2007.10.001. Epub 2007 Oct 11.
The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.
左旋多巴（l-DOPA）诱发的运动障碍和运动波动的出现是帕金森病（PD）中的一个主要临床问题。虽然有人提出l-DOPA的每日剂量可能起关键作用，但l-DOPA剂量与运动并发症发生之间的联系尚未得到探索。利用PD的实验模型，我们最近证明，长期l-DOPA治疗导致异常不自主运动（AIMs）的诱导会改变皮质纹状体双向突触可塑性。事实上，运动障碍动物缺乏逆转先前诱导的长期增强（LTP）的能力。这种缺乏去增强作用与消除不必要的运动信息的缺陷有关。在这里，以两种不同剂量对偏侧帕金森病大鼠进行慢性l-DOPA治疗，随后从纹状体棘状神经元进行电生理记录。低剂量和高剂量的l-DOPA均恢复了正常的LTP，多巴胺（DA）去神经支配后LTP被破坏。然而，在慢性治疗结束时，虽然低剂量l-DOPA仅在一半的大鼠中诱导出AIMs，但高剂量在所有接受治疗的动物中均引起了运动并发症。有趣的是，运动并发症的剂量相关表达与突触去增强作用的缺乏有关。我们的研究提供了进一步的实验证据，以支持l-DOPA的每日剂量与运动并发症的诱导之间的直接相关性，并在突触去增强作用的缺乏与AIMs的表达之间建立了关键的病理生理联系。
