Metabotropic glutamate receptors in Parkinson's disease

Parkinson's disease (PD) is a complex disorder that leads to alterations in multiple neurotransmitter systems, notably glutamate. As such, several drugs acting at glutamatergic receptors have been assessed to alleviate the manifestation of PD and treatment-related complications, culminating with the approval of the N-methyl-d-aspartate (NMDA) antagonist amantadine for l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. Glutamate elicits its actions through several ionotropic and metabotropic (mGlu) receptors. There are 8 sub-types of mGlu receptors, with sub-types 4 (mGlu₄) and 5 (mGlu₅) modulators having been tested in the clinic for endpoints pertaining to PD, while sub-types 2 (mGlu₂) and 3 (mGlu₃) have been investigated in pre-clinical settings. In this book chapter, we provide an overview of mGlu receptors in PD, with a focus on mGlu₅, mGlu₄, mGlu₂ and mGlu₃ receptors. For each sub-type, we review, when applicable, their anatomical localization and possible mechanisms underlying their efficacy for specific disease manifestation or treatment-induced complications. We then summarize the findings of pre-clinical studies and clinical trials with pharmacological agents and discuss the potential strengths and limitations of each target. We conclude by offering some perspectives on the potential use of mGlu modulators in the treatment of PD.