Abstract
We have recently shown that activation of metabotropic glutamate 2 (mGlu2) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson's disease (PD). We have obtained these benefits with the mGlu2-positive allosteric modulator (PAM) LY-487,379 and the mGlu2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected L-DOPA in combination with either vehicle, LY-487,379 (10mg/kg), LY-341,495 (1mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected L-DOPA in combination with either vehicle, LY-354,740 (1mg/kg), LY-341,495 (1mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P < 0.001) and PLBs (by 44% and 39%, P < 0.01 and P < 0.001) when compared to vehicle treatment. When LY-487,379 and LY-354,740 were administered concurrently with LY-341,495, the anti-dyskinetic and anti-psychotic benefits were abolished. When administered with L-DOPA in the absence of LY-487,379 and LY-354,740, LY-341,495 did not worsen dyskinesia or PLBs and did not hamper L-DOPA anti-parkinsonian action. Our results indicate that the anti-dyskinetic and anti-psychotic effects of mGlu2-positive allosteric modulation and mGlu2/3 orthosteric stimulation are reversed by mGlu2/3 orthosteric blockade.
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