Objective: To determine whether the therapeutic effect of serotonin 2A (5-HT_2A) receptor antagonism on dyskinesia and psychosis may be reversed by orthosteric antagonism of metabotropic glutamate 2 and 3 (mGlu_2/3) receptors.

Background: Previous experiments from our lab have shown that the highly selective 5-HT_2A 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 mGlu_2/3 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-HT_2A 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-HT_2A 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.

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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/