Objective: To determine the effectiveness of highly-selective metabotropic glutamate 2 receptor (mGluR₂) activation at alleviating and preventing the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia.

Background:

Chronic administration of L-DOPA, the current mainstay of Parkinson’s disease (PD) treatment, is marred by motor complications such as dyskinesia. Modulation of glutamatergic transmission with amantadine is an effective strategy to alleviate dyskinesia. Here, we hypothesised that mGluR₂ activation is a new and efficacious way to reduce the severity of established, and prevent the development of, dyskinesia.

Methods:

Female Sprague-Dawley rats were rendered hemi-parkinsonian by administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Two sets of experiments were then conducted. In the first set, rats were primed with L-DOPA to elicit stable and reproducible axial, limbs and oro-lingual (ALO) abnormal involuntary movements (AIMs), after which they were administered L-DOPA in combination with the highly-selective mGluR₂ positive allosteric modulator LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg) and ALO AIMs severity was determined. In the second series of experiments, rats were divided in 2 groups, L-DOPA/vehicle and L-DOPA/LY-487,379 0.1 mg/kg, after which they were primed for 3 weeks. After a 2-day washout period, they were all administered an acute challenge of L-DOPA and ALO AIMs severity was assessed. The effect of LY-487,379 on L-DOPA anti-parkinsonian action was determined by the cylinder test.

Results: In combination with L-DOPA, LY-487,379 0.1 mg/kg significantly diminished the severity of ALO AIMs, by 40% (P < 0.05), compared to L-DOPA alone. We also demonstrate that LY-487,379 0.1 mg/kg, started concurrently with L-DOPA, attenuates the priming process leading to the development of dyskinesia, when compared to L-DOPA alone, by 82% (P < 0.05). Importantly, administration of LY-487,379 did not hinder L-DOPA anti-parkinsonian action.

Conclusions: These results suggest that selective mGluR₂ activation is a new and effective therapeutic strategy to reduce the severity, and attenuate the development, of L-DOPA-induced dyskinesia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-highly-selective-mglur2-positive-allosteric-modulator-ly-487379-alleviates-l-dopa-induced-dyskinesia-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/