Distinct anti-dyskinetic effects of amantadine and group II metabotropic glutamate receptor agonist LY354740 in a rodent model: An electrophysiological perspective

NEUROBIOLOGY OF DISEASE

卷:139

Article

Zheng, Cong¹  Xu, Yan¹  Chen, Guiqin²  Tan, Yang¹  Zeng, Weiqi¹  Wang, Ji¹  Cheng, Chi¹  Yang, Xiaoman¹  Nie, Shuke²  Zhang, Zhentao²  Cao, Xuebing¹ 

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Neurol, Wuhan 430022, Peoples R China

[2] Wuhan Univ, Dept Neurol, Renmin Hosp, Wuhan 430060, Peoples R China

关键词: Parkinson's disease;    Dyskinesia;    mGluR2/3;    LY354740;    Amantadine;   

DOI  :  10.1016/j.nbd.2020.104807

来源: Elsevier

【 摘 要 】

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 gamma oscillation (h gamma) 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 hy 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.