Combined mGlu2 orthosteric stimulation and positive allosteric modulation alleviates l-DOPA-induced psychosis-like behaviours and dyskinesia in the parkinsonian marmoset

In recent studies performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD), we have demonstrated that activation of the metabotropic glutamate 2 (mGlu2) receptor with the orthosteric agonist (OA) LY-354,740 and the positive allosteric modulator (PAM) LY-487,379 is effective at alleviating both dyskinesia and psychosis-like behaviours (PLBs) triggered by the administration of l-3,4-dihydroxyphenylalanine (l-DOPA). Because mGlu2 OAs and PAMs bind to different sites on the receptor, we hypothesised that greater reductions of dyskinesia and PLBs would be obtained upon concurrent administration of LY-354,740 and LY-487,379. In experiments performed in six MPTP-lesioned marmosets, we administered LY-354,740 (0.1 mg/kg), LY-487,379 (1 mg/kg), LY-354,740 (0.1 mg/kg) + LY-487,379 (1 mg/kg), or vehicle, in combination with l-DOPA and determined the effect of each treatment on dyskinesia, PLBs, and parkinsonism. When compared to vehicle, LY-354,740 and LY-487,379, administered alone or concurrently, significantly reduced dyskinesia. The combination LY-354,740 + LY-487,379 provided mild additional benefit when compared to LY-487,379 alone, but not compared to LY-354,740. For PLBs, when compared to vehicle treatment, LY-354,740, LY-487,379, and combination thereof all alleviated the abnormal behaviours, but the combination LY-354,740 + LY-487,379 did not provide greater relief than either drug alone. The anti-parkinsonian effect of l-DOPA was not altered by any of the treatments. Our results provide further evidence that mGlu2 activation might be a novel approach to treat l-DOPA-induced dyskinesia and dopaminergic psychosis in PD. However, they do not suggest that greater therapeutic effect would be achieved upon combining an mGlu2 OA and an mGlu2 PAM.