Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada.
Neurodegenerative Disease Group, Montreal Neurological Institute, Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
Neuropharmacology. 2021 Mar 15;186:108465. doi: 10.1016/j.neuropharm.2021.108465. Epub 2021 Jan 22.
Antagonising the serotonin 2A (5-HT) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu) receptors, in which 5-HT blockade and mGlu activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (l-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we hypothesised that concurrent 5-HT antagonism and mGlu activation would provide greater anti-dyskinetic and anti-psychotic benefits than either approach alone. We conducted 3 series of experiments in the MPTP-lesioned marmoset. In the first series of experiments, the mGlu positive allosteric modulator LY-487,379 and the 5-HT antagonist EMD-281,014, either alone or in combination, were added to l-DOPA. In the second series of experiments, the mGlu orthosteric agonist LY-354,740 and EMD-281,014, either alone or in combination, were added to l-DOPA. In the last series of experiments, we investigated whether mGlu blockade would diminish the effects of antagonising 5-HT receptors. To this end, the mGlu orthosteric antagonist LY-341,495 and EMD-281,014, either alone or in combination, were added to l-DOPA. We found that the anti-dyskinetic effect of the combination LY-487,379/EMD-281,014 was greater than the ones conferred by LY-487,379 (by 35%, P < 0.05) and EMD-281,014 (by 38%, P < 0.01). The anti-dyskinetic and anti-psychotic effects of the combination LY-354,740/EMD-281,014 were also greater than the ones conferred by LY-354,740 (by 57% for dyskinesia and 54% for PLBs, both P < 0.001) and EMD-281,014 (by 61% for dyskinesia and 53% for PLBs, both P < 0.001). The anti-parkinsonian action of l-DOPA was maintained with all treatments. Lastly, the addition of LY-341,495 abolished the therapeutic effects of EMD-281,014 on dyskinesia and PLBs. Our results suggest that mGlu activation may enhance the anti-dyskinetic and anti-psychotic effects of 5-HT blockade and could provide relief to PD patients with dyskinesia and psychotic symptoms beyond what can be achieved with current therapies.
拮抗 5-羟色胺 2A（5-HT）受体是缓解帕金森病（PD）运动障碍和精神病的有效方法。然而，先前的研究表明，这种方法的效果可能存在限制。5-HT 受体与代谢型谷氨酸 2（mGlu）受体形成异二聚体，其中 5-HT 阻断和 mGlu 激活在下游信号转导水平产生等效的作用。我们之前已经表明，mGlu 激活可减少 L-3,4-二羟基苯丙氨酸（l-DOPA）诱导的运动障碍和精神病样行为（PLBs），在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的灵长类动物中。在这里，我们假设同时进行 5-HT 拮抗和 mGlu 激活将比单独使用任何一种方法提供更大的抗运动障碍和抗精神病益处。我们在 MPTP 损伤的狨猴中进行了 3 系列实验。在第一系列实验中，mGlu 正变构调节剂 LY-487,379 和 5-HT 拮抗剂 EMD-281,014 单独或联合添加到 l-DOPA 中。在第二系列实验中，mGlu 正变构激动剂 LY-354,740 和 EMD-281,014 单独或联合添加到 l-DOPA 中。在最后一系列实验中，我们研究了 mGlu 阻断是否会降低拮抗 5-HT 受体的效果。为此，我们添加了 mGlu 变构拮抗剂 LY-341,495 和 EMD-281,014 到 l-DOPA 中。我们发现，LY-487,379/EMD-281,014 联合治疗的抗运动障碍效果大于 LY-487,379（增加 35%，P<0.05）和 EMD-281,014（增加 38%，P<0.01）。LY-354,740/EMD-281,014 联合治疗的抗运动障碍和抗精神病效果也大于 LY-354,740（运动障碍增加 57%，精神病样行为增加 54%，均 P<0.001）和 EMD-281,014（运动障碍增加 61%，精神病样行为增加 53%，均 P<0.001）。所有治疗方法均维持 l-DOPA 的抗帕金森病作用。最后，添加 LY-341,495 消除了 EMD-281,014 对运动障碍和精神病样行为的治疗作用。我们的结果表明，mGlu 激活可能增强 5-HT 阻断的抗运动障碍和抗精神病作用，并为运动障碍和精神病症状的 PD 患者提供比当前治疗方法更有效的缓解。
