Abstract

Pharmacologic or genetic blockade of metabotropic glutamate mGlu5 receptors (mGluR5) has been shown to attenuate parkinsonian motor deficits and protect nigrostriatal neurons from damage in the acute MPTP model of Parkinson's disease (PD), suggesting that therapeutically targeting the mGluR5 receptor may offer a novel approach to improving motor symptoms and/or slowing neurodegeneration in PD. This study further explored the neuroprotective potential of targeting mGluR5 receptors. We examined the behavioral and neurochemical effects of receptor elimination on toxicity induced by intra-striatal application of 6-hydroxydopamine (6-OHDA), thought to represent a comparatively progressive model of PD. mGluR5 knockout (KO) mice and wild-type (WT) littermates received unilateral 6-OHDA infusions. Reflecting the imbalance expected following unilateral infusion, WT but not KO mice demonstrated predominantly ipsilateral forepaw use and robust ipsilateral amphetamine-induced rotation. Further, performance on the vertical pole descent task was profoundly impaired in WT mice, while KO mice completed the task significantly faster. Consistent with the behavioral observations, neurochemical analyses of striatal dopamine depletion showed significantly diminished severity in KO mice with only 64% of striatal dopamine lost, compared to 92% in WT mice. The absence of brain mGluR5 receptors in living KO mice was verified using positron emission tomography (PET). Our findings substantiate the key role of mGluR5 receptors in animal models of PD, strengthening the rationale for the development of mGluR5 antagonists for their neuroprotective, as well as symptomatic, benefit.