Objective: To assess the effects of different doses of the metabotropic glutamate 2 and 3 (mGlu2/3) orthosteric antagonist (OA) LY-341,495 on the anti-dyskinetic and anti-psychotic actions of the mGlu2 positive allosteric modulator (PAM) LY-487,379.
Background: We have previously demonstrated that LY-341,495 reversed the anti-dyskinetic and anti-psychotic benefits of LY-487,379. There have been reports of a cross-talk between mGlu3 and mGlu5 receptors. As antagonising mGlu5 receptors is a promising approach to reduce dyskinesia, it is possible that mGlu3 blockade might also diminish dyskinesia severity. Here, we investigated whether a potential mGlu3 antagonistic effect with a higher dose of LY-341,495 would oppose the mGlu2-antagonistic effect obtained with a lower dose, resulting in a lower reversal of the anti-dyskinetic benefit of LY-487,379.
Method: Six common marmosets were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections, after which dyskinesia and psychosis-like behaviours (PLBs) were induced by daily administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Marmosets then received the following treatments, in combination with L-DOPA, in a random order: vehicle/vehicle, LY-487,379/vehicle, LY-487,379/LY-341,495 1 mg/kg and LY-487,379/LY-341,495 3 mg/kg, after which dyskinesia, PLBs and parkinsonism were rated. The dose of LY-487,379 was 1 mg/kg, based upon prior studies.
Results: LY-487,379 diminished the severity of global dyskinesia, by 39% (P < 0.001). When LY-341,495 3 mg/kg was added to LY-487,379, the reduction of dyskinesia was only 8% (P < 0.05). When LY-487,379 was added to L-DOPA, PLBs were diminished by 36% (P < 0.001), while the remaining reduction was only 2% after LY-341,495 3 mg/kg was added (P > 0.05). Lastly, when LY-487,379 was administered with L-DOPA, global parkinsonism was diminished by 15% (P < 0.05); this additional anti-parkinsonian benefit was no longer present after LY-341,495 was added, regardless of the dose.
Conclusion: A theoretically beneficial mGlu3 antagonistic effect may not be sufficient to overcome a deleterious mGlu2 antagonistic effect, when a dual mGlu2/3 OA is added to a mGlu2 PAM, suggesting that, in vivo, action at mGlu2 receptors might supersede that of mGlu3 receptors in dyskinesia and psychosis in PD.
To cite this abstract in AMA style:S. Nuara, J. Gourdon, P. Huot. A dose-response study of the effect of the mGlu2/3 orthosteric antagonist LY-341,495 on the anti-dyskinetic and anti-psychotic effect of the mGlu2 positive allosteric modulator LY-487,379 in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/a-dose-response-study-of-the-effect-of-the-mglu2-3-orthosteric-antagonist-ly-341495-on-the-anti-dyskinetic-and-anti-psychotic-effect-of-the-mglu2-positive-allosteric-modulator-ly-487379-in-the-mptp/. Accessed December 1, 2023.
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