Objective: To determine whether pharmacological inhibition of metabotropic glutamate receptor type 5 (mGluR5) can improve dyskinesias mediated by D1- or D2-type dopamine (DA) receptors (D1R and D2R, respectively) in parkinsonian mice.

Background: L-DOPA-induced dyskinesia (LID) is reduced by a selective mGluR5 antagonist (Rascol et al., Parkinsonism Relat. Disord. 2014). However, the mechanisms underlying the antidyskinetic effects of this class of drugs remains unclear. In this study, the question has been explored by evaluating the effects of the selective mGluR5 antagonist MTEP on dyskinesias evoked by D1R or D2R agonists, which conceivably depend on different neuronal pathways.

Methods: Mice having a selective knockdown of mGluR5 in D1R-expressing striatal neurons (mGluR5^KD-D1; Novak et al. J. Neurosci. 2010) and Wild type (Wt) littermates sustained a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal projections. Mice were allotted to different treatment groups, receiving either L-DOPA, the D1R-like agonist SKF38393 or the D2R-like agonist Quinpirole. The potential antidyskinetic effect of MTEP was evaluated in each treatment group.

Results: In Wt mice, the selective mGluR5 antagonist MTEP ameliorated dyskinesias induced by L-DOPA (p < 0.01 vs. vehicle + L-DOPA) and SKF38393 (p < 0.01 vs. vehicle + SKF38393), but not Quinpirole. Compared to Wt controls, mGluR5^KD-D1 mice displayed lower levels of dyskinesia when treated with either L-DOPA or SKF38393 (both, p < 0.05 vs. Wt mice). In contrast, Quinpirole elicited comparable levels of dyskinesia in both mGluR5^KD-D1 and Wt mice. Interestingly, challenging mGluR5^KD-D1 mice with MTEP did not further reduce L-DOPA- and SKF38393-induced dyskinesia to significant levels.

Conclusions: These results are the first to substantiate that the anti-dyskinetic effect of mGluR5 antagonism is exerted on dyskinesias caused by D1R, while it is ineffective on D2R-mediated dyskinesias. This suggests the need for future treatments to take into account the patient-specific involvement of D1R or D2R in their dyskinesias.

References: Rascol et al., Parkinsonism Relat. Disord. 2014

Novak et al. J. Neurosci. 2010

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacological-modulation-of-mglur5-improves-dyskinesias-mediated-by-d1-but-not-d2-receptor-stimulation/