Pharmacological Modulation of the Striatal mGluR5–NR2B Association Attenuates L-DOPA-Induced Dyskinesia in 6-OHDA Lesioned Parkinsonian Rats

The clinical utility of L-DOPA is severely limited by the development of L-DOPA-induced dyskinesia (LID). Although metabotropic glutamate receptor 5 (mGluR5) antagonists alleviate LID, the underlying molecular mechanisms, particularly those involving striatal glutamate receptor crosstalk, remain incompletely understood. This study investigated the role of the striatal association between mGluR5 and the NMDA receptor subunit NR2B in LID pathogenesis. We observed aberrant elevation of the mGluR5-NR2B interactions in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned parkinsonian rats exhibiting LID. Administration of the mGluR5 antagonist MTEP or the NMDA receptor antagonist MK-801 reduced the co-immunoprecipitated association, reduced the synaptic association of mGluR5 with NR2B, and markedly attenuated LID severity. Mechanistically, the decoupling of these receptors was accompanied by decreased ERK1/2 phosphorylation, reduced PKC protein expression, and decreased L-DOPA-induced c-fos and prodynorphin mRNA levels. Furthermore, abnormal involuntary movement (AIM) scores significantly correlated with the extent of NR2B-mGluR5 interaction and downstream signaling activation. These findings suggest that increased mGluR5-NR2B association is associated with LID and may contribute to its expression. Consequently, the therapeutic efficacy of MTEP or MK-801 is likely mediated by reducing this receptor interaction and downstream signaling, highlighting a potential molecular target for LID treatment.