Abstract：
Parkinson\'s disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson\'s disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson\'s disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA\'s pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
摘要：
帕金森病是由黑质致密区多巴胺能神经元的选择性脆弱性和细胞丢失引起的，因此,纹状体多巴胺耗竭.在帕金森病治疗中，多巴胺的损失是通过服用L-DOPA来抵消的，最初对改善运动症状有效，但是随着时间的推移会导致无法控制的生涩运动的副作用，称为L-DOPA诱导的运动障碍。迄今为止,没有有效的治疗运动障碍存在。多巴胺能和5-羟色胺能系统是内在联系的，近年来,已经确定了突触前5-HT1a/b受体在L-DOPA诱导的运动障碍中的作用。我们假设突触后5-羟色胺受体可能起作用，并研究了5-HT4受体调节对帕金森病单侧6-OHDA小鼠模型运动症状和L-DOPA诱导的运动障碍的影响。给予5-HT4受体部分激动剂RS67333，减少L-DOPA诱导的运动障碍，而不改变L-DOPA的前动力学效应。在背外侧纹状体，我们发现5-HT4受体主要在含有D2R的中等多刺神经元中表达，多巴胺耗竭和L-DOPA治疗改变了其表达。我们进一步表明，5-HT4受体激动不仅减少L-DOPA诱导的运动障碍，而且还增强了纹状体中等棘突神经元中cAMP-PKA途径的激活。一起来看,我们的研究结果表明,突触后5-羟色胺受体5-HT4的激动作用可能是减少L-DOPA诱导的运动障碍的一种新的治疗方法.
