In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu₂) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of l-3,4-dihydroxyphenylalanine (l-DOPA). Because mGlu₂ OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with l-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of l-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu₂ activation might be a novel approach to treat l-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu₂ OA and an mGlu₂ PAM.

在最近对帕金森病 (PD) 的 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 损伤的狨猴模型进行的研究中，我们证明了代谢型谷氨酸 2 (mGlu ₂ ) 受体与正构激动剂 (OA) LY-354,740 和正变构调节剂 (PAM) LY-487,379 可有效缓解由施用l -3,4-二羟基苯丙氨酸引发的运动障碍和精神病样行为 (PLB) （l-多巴）。因为 mGlu ₂OAs 和 PAMs 与受体上的不同位点结合，我们假设同时施用 LY-354,740 和 LY-487,379 会更大程度地减少运动障碍和 PLB。在六只 MPTP 损伤的狨猴中进行的实验中，我们给予 LY-354,740 (0.1 mg/kg)、LY-487,379 (1 mg/kg)、LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg) )，或车辆，与l组合-DOPA 并确定每种治疗对运动障碍、PLB 和帕金森综合征的影响。与载体相比，LY-354,740 和 LY-487,379，单独或同时给药，显着减少运动障碍。与单独的 LY-487,379 相比，LY-354,740 + LY-487,379 的组合提供了轻微的额外好处，但与 LY-354,740 相比则不然。对于 PLB，与媒介物治疗相比，LY-354,740、LY-487,379 及其组合均减轻了异常行为，但 LY-354,740 + LY-487,379 组合并未比单独使用任何一种药物提供更大的缓解。任何治疗都没有改变l-多巴的抗帕金森病作用。我们的结果进一步证明 mGlu ₂激活可能是治疗l- PD 中多巴诱导的运动障碍和多巴胺能精神病。然而，他们并没有建议将 mGlu ₂ OA 和 mGlu ₂ PAM结合使用会获得更大的治疗效果。