Session Information
Date: Monday, September 23, 2019
Session Title: Neuropharmacology
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: We seek 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 positive allosteric modulator LY-487,379.
Background: We have recently discovered that positive allosteric modulation of mGlu2 receptors with LY-487,379 is a therapeutic approach that reduces 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-487,379.
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-487,379, L-DOPA/LY-341,495 and L-DOPA/LY-487,379/LY-341,495, after which the severity of dyskinesia, PLBs and parkinsonism were scored.
Results: We found that mGlu2 positive allosteric modulation with LY-487,379 significantly reduced the severity of L-DOPA-induced dyskinesia and PLBs, compared to L-DOPA alone. mGlu2/3 orthosteric blockade with LY-341,495 did not exacerbate either of L-DOPA-induced dyskinesia or PLBs, when compared to L-DOPA alone. However, when LY-487,379 and LY-341,495 were added to L-DOPA simultaneously, the anti-dyskinetic and anti-psychotic effects of LY-487,379 were no longer present.
Conclusion: Our results indicate that the beneficial effects of mGlu2 positive allosteric modulation on dyskinesia and PLBs can be reversed upon orthosteric blockade of mGlu2/3 receptors, providing pharmacological validation of the mGlu2-selective mechanism whereby LY-487,379 acts to alleviate both dyskinesia and psychosis in the MPTP-lesioned non-human primate.
To cite this abstract in AMA style:
A. Hamadjida, S. Nuara, J. Gourdon, P. Huot. The mGlu2/3 orthosteric antagonist LY-341,495 abolishes the anti-dyskinetic and anti-psychotic effects of the mGlu2 positive allosteric modulator LY-487,379 in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/the-mglu2-3-orthosteric-antagonist-ly-341495-abolishes-the-anti-dyskinetic-and-anti-psychotic-effects-of-the-mglu2-positive-allosteric-modulator-ly-487379-in-the-mptp-lesioned-marmoset/. Accessed December 10, 2024.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-mglu2-3-orthosteric-antagonist-ly-341495-abolishes-the-anti-dyskinetic-and-anti-psychotic-effects-of-the-mglu2-positive-allosteric-modulator-ly-487379-in-the-mptp-lesioned-marmoset/