Distinct anti-dyskinetic effects of amantadine and group II metabotropic T glutamate receptor agonist LY354740 in a rodent model: An electrophysiological perspective
Distinct anti-dyskinetic effects of amantadine and group II metabotropic T glutamate receptor agonist LY354740 in a rodent model: An electrophysiological perspective
复制标题
金刚烷胺和 II 族代谢型 T 谷氨酸受体激动剂 LY354740 在啮齿动物模型中的独特抗运动障碍作用：电生理学角度
DOI：
10.1016/j.nbd.2020.104807
复制
发表时间：
2020
影响因子：
6.1
通讯作者：
Xuebing Cao
中科院分区：
文献类型：
--
作者：
Cong Zheng;Yan Xu;Guiqin Chen;Yang Tan;Weiqi Zeng;Ji Wang;Chi Cheng;Xiaoman Yang;Shuke Nie;Zhentao Zhang;Xuebing Cao
左旋多巴诱导的运动障碍（LID）是帕金森病长期多巴胺替代治疗的主要并发症。特征性神经振荡和纹状体投射神经元（SPNs）异常活动是LID的典型病理事件，如果充分描述，将是评估新型抗运动障碍方法的可靠生物标志物。谷氨酸失调在LID的发展中起着关键作用，并且II组代谢型谷氨酸受体（mGluR 2/3）被认为调节突触前末梢上谷氨酸的释放并抑制突触后兴奋。然而，调节mGluR 2/3的抗运动障碍作用仍不清楚。在这项研究中，单侧多巴胺能损伤的大鼠用L-DOPA（12 mg/kg，i. p.）7天，而运动行为与体内电生理学分析LFP和初级运动皮层和背外侧纹状体中的单细胞活性相关。我们的研究表明，随着LID的建立，高γ振荡（hγ）在LID期间占主导地位，SPN对多巴胺的不稳定反应的数量增加，并且这些振荡模式与尖峰活动之间的一致性也增加。我们发现，预先给予NMDA受体拮抗剂金刚烷胺（amantadine，AMAN）60 mg/kg，可显著减少异常不自主运动（AIMs），同时减少hγ振荡，尤其是减少SPN的不稳定反应。相比之下，mGluR 2/3激动剂LY 354740 12 mg/kg，i. p.（LY）显著缩短了LID的持续时间，但仅表现出减弱LID强度或逆转SPN反应的微弱作用。总之，结果表明PD大鼠模型中的AIM与异常皮质纹状体信号传导相关，其可以通过NMDAR拮抗作用比mGluR 2/3激动作用更有效地逆转。
L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism.