Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the midbrain and shows motor dysfunctions. Zonisamide (ZNS, 1,2-benzisoxazole-3-methanesulfonamide), which was originally developed as an antiepileptic drug, was also found to have beneficial effects on motor symptoms in PD. In the current study, we have investigated the behavioral and physiological effects of ZNS on L-DOPA-induced dyskinesia (LID) in PD model mice. Chronic administration of L-DOPA plus ZNS in PD model mice was shown to increase the duration and severity of LID compared with PD model mice that were treated with L-DOPA alone. To elucidate the neural mechanism of the effects of ZNS on LID, we examined neuronal activity in the output nuclei of the basal ganglia, i.e., the substantia nigra pars reticulata (SNr). Chronic administration of L-DOPA plus ZNS in PD mice decreased the firing rate in the SNr while they showed apparent LID. In addition, chronic treatment of L-DOPA plus ZNS in PD mice changed cortically evoked responses in the SNr during LID. In the control state, motor cortical stimulation induces the triphasic response composed of early excitation, inhibition, and late excitation. In contrast, L-DOPA plus ZNS-treated PD mice showed longer inhibition and reduced late excitation. Previous studies proposed that inhibition in the SNr is derived from the direct pathway and releases movements, and that late excitation is derived from the indirect pathway and stops movements. These changes of the direct and indirect pathways possibly underlie the effects of ZNS on LID.

中文翻译：

---

唑尼沙胺对帕金森氏病模型小鼠的L-DOPA诱导的运动障碍的影响。

帕金森氏病（PD）是由中脑多巴胺能神经元缺失引起的神经退行性疾病，并表现出运动功能障碍。唑尼沙胺（ZNS，1,2-苯并恶唑-3-甲磺酰胺）最初被开发为抗癫痫药，也被发现对帕金森氏症的运动症状具有有益作用。在当前的研究中，我们已经研究了ZNS对PD模型小鼠中L-DOPA诱导的运动障碍（LID）的行为和生理作用。与仅用L-DOPA治疗的PD模型小鼠相比，在PD模型小鼠中长期给予L-DOPA加ZNS可以增加LID的持续时间和严重程度。为了阐明ZNS对LID的影响的神经机制，我们检查了基底神经节输出核（即黑质网状组织（SNr））的输出核中的神经元活性。在PD小鼠中长期服用L-DOPA加ZNS可以降低SNr的放电率，但它们表现出明显的LID。此外，在LID期间，对PD小鼠进行L-DOPA加ZNS的长期治疗改变了SNr的皮质诱发反应。在控制状态下，运动皮层刺激引起由早期激发，抑制和晚期激发组成的三相反应。相比之下，L-DOPA加ZNS处理的PD小鼠表现出更长的抑制作用，并减少了晚期兴奋。先前的研究提出，对SNr的抑制作用源自直接途径并释放运动，而后期激发则源自间接途径并阻止运动。直接和间接途径的这些变化可能是ZNS对LID影响的基础。