Category: Neuropharmacology
Objective: To determine whether the therapeutic effect of serotonin 2A (5-HT2A) receptor antagonism on dyskinesia and psychosis may be reversed by orthosteric antagonism of metabotropic glutamate 2 and 3 (mGlu2/3) receptors.
Background: Previous experiments from our lab have shown that the highly selective 5-HT2A antagonist EMD-281,014 alleviates 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. We also demonstrated that these benefits were reversed by co-administering the mGlu2/3 antagonist LY-341,495. Here, we investigated if higher doses of LY-341,495, associated with a higher mGlu3 antagonistic effect, would mitigate the deleterious effect of antagonising mGlu2 receptors, in combination with a 5-HT2A antagonist.
Method: Six MPTP-lesioned marmosets with severe dyskinesia and PLBs were administered the following treatments, in combination with L-DOPA, in a random fashion: vehicle/vehicle, EMD-281,014/vehicle, EMD-281,014/LY-341,495 1 mg/kg and EMD-281,014/LY-341,495 3 mg/kg. Dyskinesia, PLBs and parkinsonism were then rated. The dose of EMD-281,014 was 0.03 mg/kg, based on prior studies.
Results: Compared to L-DOPA alone, EMD-281,014 diminished the severity of global dyskinesia, by 40% (P < 0.001). When LY-341,495 was added to EMD-281,014, the reduction of dyskinesia progressively decreased and was only 12% with the dose of 3 mg/kg, when compared to L-DOPA/vehicle (P < 0.05). When EMD-281,014 was combined to L-DOPA, PLBs were diminished by 41% (P < 0.001), while the reduction was down to 12% after LY-341,495 3 mg/kg was combined with EMD-281,014 (P < 0.05). Lastly, none of the treatments altered the anti-parkinsonian action of L-DOPA.
Conclusion: These results indicate that, when combined to a 5-HT2A antagonist, blockade of mGlu3 receptors may not be enough to overcome the deleterious effect of mGlu2 antagonism on dyskinesia and psychosis in PD. Further studies are required to determine if similar results would be obtained with an antagonist exhibiting more selectivity for mGlu3 receptors.
To cite this abstract in AMA style:
S. Nuara, J. Gourdon, P. Huot. Evaluation of the effect of adding a mGlu2/3 orthosteric antagonist to a highly selective 5-HT2A antagonist on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/evaluation-of-the-effect-of-adding-a-mglu2-3-orthosteric-antagonist-to-a-highly-selective-5-ht2a-antagonist-on-dyskinesia-and-psychosis-like-behaviours-in-the-mptp-lesioned-marmoset/. Accessed November 2, 2024.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-the-effect-of-adding-a-mglu2-3-orthosteric-antagonist-to-a-highly-selective-5-ht2a-antagonist-on-dyskinesia-and-psychosis-like-behaviours-in-the-mptp-lesioned-marmoset/