Concurrent mGlu2-mGlu4 receptor positive allosteric modulation for L-DOPA-induced treatment-induced complications in the parkinsonian marmoset.

The treatment of advanced Parkinson's disease (PD) remains challenging, with few options to address motor fluctuations and dyskinesia simultaneously. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors may be a therapeutic option that could alleviate both fluctuations and dyskinesia. mGlu4 receptors form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, suggesting that additive anti-parkinsonian and antidyskinetic could be obtained upon dual mGlu2-mGlu4 positive allosteric modulation. Here, the mGlu2 positive allosteric modulator (PAM) LY-487,379 and the mGlu4 PAM ADX-88178 were administered, either alone or together, in combination with L-3,4-dihydroxyphenylalanine (L-DOPA), to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, after which the severity of parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) was assessed. We discovered that each of LY-487,379 and ADX-88178 enhanced the anti-parkinsonian action of L-DOPA and reduced dyskinesia severity when administered separately; when administered concurrently, the resulting anti-parkinsonian (P < 0.001) and anti-dyskinetic (P < 0.01) effects were greater than when both molecules were administered separately. LY-487,379, but not ADX-88178, alleviated L-DOPA-induced PLBs; when the two compounds were administered simultaneously, the resulting anti-psychotic benefit was greater than the effect achieved with LY-487,379 (P < 0.01). Our results indicate that dual mGlu2-mGlu4 positive allosteric modulation results in greater anti-parkinsonian and anti-dyskinetic effects than positive allosteric modulation of either target separately. In addition dual mGlu2-mGlu4 positive allosteric modulation enhances the anti-psychotic effect of selective mGlu2 positive allosteric modulation. Concurrent mGlu2-mGlu4 positive allosteric modulation represents a promising avenue for the treatment of complications in advanced PD.