Activation of mGlu2/3 receptors, a novel therapeutic approach to alleviate dyskinesia and psychosis in experimental parkinsonism

Selective blockade of serotonin 2A (5-HT2A) receptors is a promising strategy to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and has shown efficacy in a Phase III clinical trial for dopaminergic psychosis in Parkinson's disease (PD). However, pre-clinical and clinical evidence suggest that, while this approach may be effective and well tolerated, there might be a ceiling beyond which no further therapeutic benefit might be achieved. There is mounting evidence that 5-HT2A receptors form a functional hetero-complex with metabotropic glutamate 2 (mGlu(2)) receptors, with antagonism of 5-HT2A receptors and activation of mG1u(2) receptors producing similar effects on the Gi/Gq signalling ratio at the intra-cellular level. Based on this interaction between 5-HT2A and mGlu(2) receptors, we hypothesised that activation of mG1u 2 receptors would alleviate dyskinesia and psychosis in PD. LY-354,740 is a selective mG1u(2/3) orthosteric agonist that was previously tested in the clinic. In experiments conducted in the 6-hydroxydopamine (6-OHDA)-lesioned rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset, we found that mG1u(2/3) activation with LY-354,740 significantly reduced the expression of dyskinesia and psychosis-like behaviours, while simultaneously enhancing L-DOPA therapeutic benefit. Moreover, mG1u(2/3) activation with LY-354,740 attenuated the development of dyskinesia. These data indicate that activation of mG1u(2/3) receptors is a therapeutic strategy that may provide relief for both motor and-non-motor treatment-related complications in PD.