We have recently shown that activation of metabotropic glutamate 2 (mGlu2) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson's disease (PD). We have obtained these benefits with the mGlu2-positive allosteric modulator (PAM) LY-487,379 and the mGlu2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected L-DOPA in combination with either vehicle, LY-487,379 (10 mg/kg), LY-341,495 (1 mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected L-DOPA in combination with either vehicle, LY-354,740 (1 mg/kg), LY-341,495 (1 mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P < 0.001) and PLBs (by 44% and 39%, P < 0.01 and P < 0.001) when compared to vehicle treatment. When LY-487,379 and LY-354,740 were administered concurrently with LY-341,495, the anti-dyskinetic and anti-psychotic benefits were abolished. When administered with L-DOPA in the absence of LY-487,379 and LY-354,740, LY-341,495 did not worsen dyskinesia or PLBs and did not hamper L-DOPA anti-parkinsonian action. Our results indicate that the anti-dyskinetic and anti-psychotic effects of mGlu2-positive allosteric modulation and mGlu2/3 orthosteric stimulation are reversed by mGlu2/3 orthosteric blockade.

中文翻译：

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mGlu2/3 拮抗剂 LY-341,495 可逆转 mGlu2 激活剂 LY-487,379 和 LY-354,740 在 MPTP 损伤的狨猴中的抗运动障碍和抗精神病作用。

我们最近表明，通过正变构调节和正位刺激激活代谢型谷氨酸 2 (mGlu2) 受体是一种减少 L-3,4-二羟基苯丙氨酸 (L-DOPA) 诱发的帕金森病 (PD) 运动障碍和多巴胺能精神病的新方法）。我们通过 mGlu2 阳性变构调节剂 (PAM) LY-487,379 和 mGlu2/3 正构激动剂 (OA) LY-354,740 在 1-methyl-4-phenyl-1,2,3 的实验中获得了这些好处， 6-四氢吡啶 (MPTP) 损伤的狨猴。在这里，我们试图通过评估 LY-487,379 和 LY-354,740 的益处是否会被 mGlu2/3 正位拮抗剂 LY-341,495 逆转，在药理学上表征 LY-487,379 和 LY-354,740 的抗运动障碍和抗精神病作用。表现出稳定的运动障碍和精神病样行为 (PLB) 的六只 MPTP 损伤的狨猴进入了实验。在第一组实验中，动物被注射了左旋多巴与媒介物 LY-487,379（10 毫克/千克）、LY-341,495（1 毫克/千克）或 LY-487,379/LY-341,495。在第二个系列的实验中，狨猴注射 L-DOPA 与媒介物 LY-354,740（1 毫克/千克）、LY-341,495（1 毫克/千克）或 LY-354,740/LY-341495。正如我们之前所证明的，与车辆相比，LY-487,379 和 LY-354,740 均减轻了运动障碍（分别减轻了 44% 和 47%，P < 0.001）和 PLB（分别减轻了 44% 和 39%，P < 0.01 和 P < 0.001）治疗。当 LY-487,379 和 LY-354,740 与 LY-341,495 同时给药时，抗运动障碍和抗精神病的益处被取消。在不存在 LY-487,379 和 LY-354,740 的情况下与 L-DOPA 一起给药时，LY-341,495 不会加重运动障碍或 PLB，也不会妨碍 L-DOPA 的抗帕金森病作用。我们的结果表明 mGlu2 阳性变构调节和 mGlu2/3 正构刺激的抗运动障碍和抗精神病作用被 mGlu2/3 正构阻断逆转。