Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson's disease

Electrophysiological evidence suggests a synergistic relationship between metabotropic (mGlu) and ionotropic (iGlu) glutamate receptors. The functional consequences of these interactions have not been investigated in neurodegenerative diseases such as in Parkinson's disease.

The goals of this study are as follows: (1) to investigate the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and dizocilpine (MK-801), antagonists at metabotropic glutamate 5 (mGlu5) and NMDA receptors, respectively, on the akinetic syndrome observed in bilateral 6-OHDA-lesioned rats; (2) to investigate if the effects of MPEP were potentiated by co-treatment with a behaviorally inactive dose of MK-801; and (3) to investigate the effects of L-DOPA alone and in combination with MPEP on the akinetic syndrome observed in 6-OHDA-lesioned rats.

The effects of the different treatments (single and co-treatment) administered for 3 weeks were measured in 6-OHDA-lesioned rats trained to release a lever rapidly after a visual stimulus onset in a simple reaction time task.

MPEP 0.75 mg/kg reversed the akinetic deficits produced by striatal dopamine depletion, while MPEP 0.375 mg/kg had no effect. Co-administration with MK-801 0.02 mg/kg, ineffective alone, failed to speed the recovery process of MPEP 0.75 mg/kg but revealed the anti-akinetic action of MPEP 0.375 mg/kg. L-DOPA 3 mg/kg alone had a potent anti-akinetic effect in 6-OHDA lesioned rats, and this effect was not potentiated by a subthreshold MPEP treatment.

These results support a critical role for mGlu5 receptor blockade in improving parkinsonian symptomatology either as a single treatment or in combination with low concentrations of L-DOPA and demonstrate an interaction between NMDA and mGluR5 in regulating these effects.