Maladaptive Plasticity of Serotonin Axon Terminals in Levodopa-Induced Dyskinesia
Maladaptive Plasticity of Serotonin Axon Terminals in Levodopa-Induced Dyskinesia
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DOI：
10.1002/ana.22097
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发表时间：
2010-11-01
影响因子：
11.2
通讯作者：
Cenci, M. Angela
中科院分区：
文献类型：
--
作者：
Rylander, Daniella;Parent, Martin;Cenci, M. Angela
目的：纹状体5-羟色胺投射通过提供不受调节的多巴胺释放来源而参与左旋多巴诱导的运动障碍。我们着手确定这些预测是否受到左旋多巴治疗的方式，将有利于发生dyskinesia.Methods：作为一个指标的终端5-羟色胺神经支配密度，我们测量了放射性配体结合到质膜5-羟色胺转运体（SERT）在左旋多巴治疗的运动障碍和nondyskinetic科目，使用脑组织从大鼠和猴模型帕金森病以及帕金森病患者。此外，striatel组织从运动障碍大鼠用于形态和超微结构分析的5-羟色胺轴突末梢，并为研究刺激[（3）H]多巴胺release.Results：在所有条件下检查，纹状体水平的SERT放射性配体结合显着升高，在运动障碍的受试者相比，nondykinetic的情况下。在大鼠纹状体中，运动障碍性左旋多巴治疗诱导5-羟色胺轴突静脉曲张发芽，具有相对较高的突触发生率。这种反应与增加去极化诱导的[（3）H]多巴胺释放和更强的释放增强brain-derived neurotrophic factor.Interpretation：这项研究提供了第一个证据表明，左旋多巴治疗诱导发芽的5-羟色胺轴突末梢，突触接触的发生率增加，和一个更大的活动依赖性增强多巴胺释放在多巴胺去神经纹状体。因此，治疗诱导的5-羟色胺神经支配的可塑性可能代表了多巴胺动力学改变的一个以前未被认识到的原因。这些结果对于了解左旋多巴药物治疗易患运动障碍的机制以及确定帕金森病运动并发症的生物标志物非常重要。神经网络2010;68：619-628
Objective: Striatal serotonin projections have been implicated in levodopa-induced dyskinesia by providing an unregulated source of dopamine release. We set out to determine whether these projections are affected by levodopa treatment in a way that would favor the occurrence of dyskinesia.Methods: As an index of terminal serotonin innervation density, we measured radioligand binding to the plasma membrane serotonin transporter (SERT) in levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from both rat and monkey models of Parkinson disease as well as parkinsonian patients. In addition, striatel tissue from dyskinetic rats was used for morphological and ultrastructural analyses of serotonin axon terminals, and for studies of stimulated [(3)H]dopamine release.Results: Across all conditions examined, striatal levels of SERT radioligand binding were significantly elevated in dyskinetic subjects compared to nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had induced sprouting of serotonin axon varicosities having a relatively high synaptic incidence. This response was associated with increased depolarization-induced [(3)H]dopamine release and with a stronger release potentiation by brain-derived neurotrophic factor.Interpretation: This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease. ANN NEUROL 2010;68:619-628