Evaluation of the effects of the mGlu2/3 antagonist LY341495 on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

Abstract

Background: We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu_2/3) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu₂ activation and serotonin 2A (5-HT_2A) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu₃ receptors, would result in a reduction of the reversal of mGlu₂ activation and 5-HT_2A blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

Methods: After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu_2/3 orthosteric agonist)/vehicle, LY354740/LY341495 1 mg/kg and LY354740/LY341495 3 mg/kg; 2. vehicle/vehicle, LY487379 (mGlu₂ positive allosteric modulator)/vehicle, LY487379/LY341495 1 mg/kg and LY487379/LY341495 3 mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT_2A antagonist)/vehicle, EMD-281,014/LY341495 1 mg/kg and EMD-281,014/LY341495 3 mg/kg.

Results: Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3 mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination.

Conclusion: These results suggest that an antagonistic effect at mGlu₃ receptors may not be sufficient to overcome the deleterious effect of mGlu₂ blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu₃ antagonist.