Session Information
Date: Monday, September 23, 2019
Session Title: Neuropharmacology
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: We aim to determine the effect of orthosteric blockade of metabotropic glutamate 2 and 3 (mGlu2/3) receptors with LY-341,495 on the anti-dyskinetic and anti-psychotic benefits conferred by the mGlu2/3 orthosteric agonist LY-354,740 (eglumegad).
Background: We have recently discovered that orthosteric stimulation of mGlu2/3 receptors with LY-354,740 reduces the severity of both L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD). Here, we hypothesised that LY-341,495 would undermine the therapeutic effects of LY-354,740.
Method: Six MPTP-lesioned marmosets exhibiting dyskinesia and PLBs upon administration of L-DOPA were administered each of the following treatments, in a random order: L-DOPA alone, L-DOPA/LY-354,740, L-DOPA/LY-341,495 and L-DOPA/LY-354,740/LY-341,495, after which the severity of dyskinesia, PLBs and parkinsonism were evaluated.
Results: We found that mGlu2/3 orthosteric stimulation with LY-354,740 significantly reduced the severity of L-DOPA-induced dyskinesia and PLBs, compared to L-DOPA alone. mGlu2/3 orthosteric blockade with LY-341,495 had no effect on the severity of L-DOPA-induced dyskinesia or PLBs, when compared to L-DOPA alone. However, when LY-354,740 and LY-341,495 were both concurrently administered with L-DOPA, the anti-dyskinetic and anti-psychotic effects of LY-354,740 were lost.
Conclusion: Our results indicate that the beneficial effects of mGlu2/3 orthosteric stimulation on L-DOPA-induced dyskinesia and PLBs can be reversed upon orthosteric blockade of mGlu2/3 receptors, providing pharmacological validation of the mGlu2/3-selective mechanism by which LY-354,740 acts to alleviate both dyskinesia and psychosis in the MPTP-lesioned primate.
To cite this abstract in AMA style:
A. Hamadjida, S. Nuara, J. Gourdon, P. Huot. LY-341,495, an mGlu2/3 antagonist, abolishes the anti-dyskinetic and anti-psychotic effects of the mGlu2/3 orthosteric agonist LY-354,740 in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/ly-341495-an-mglu2-3-antagonist-abolishes-the-anti-dyskinetic-and-anti-psychotic-effects-of-the-mglu2-3-orthosteric-agonist-ly-354740-in-the-mptp-lesioned-marmoset/. Accessed May 17, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/ly-341495-an-mglu2-3-antagonist-abolishes-the-anti-dyskinetic-and-anti-psychotic-effects-of-the-mglu2-3-orthosteric-agonist-ly-354740-in-the-mptp-lesioned-marmoset/