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Parkinson’s disease (PD) is normally associated with dopamine and other catecholamines because of the profound loss of dopaminergic neurons in the substantia nigra that is the hallmark of the disease. The need for new therapies to treat symptomatic motor and non‐motor symptoms, along with motor complications such as L‐DOPA‐induced dyskinesias (LIDs), remains an important challenge in drug discovery. Significant progress has been made recently in the development of new non‐dopaminergic treatments in the last few years, and there is substantial evidence for altered glutamate neurotransmission in PD, which may be a consequence of dopamine loss. This has generated a great deal of interest in glutamate receptor modulators for the treatment of PD. The interest initially focused on ionotropic glutamate receptors (iGluRs) both for the treatment of the symptoms of PD as well as for neuroprotective effects, and several NMDA and AMPA receptor antagonists have progressed to clinical trials. More recently, there has been substantial progress in the development of metabotropic glutamate receptor (mGluR) modulators. The recent clinical proof‐of‐concept for the treatment of LIDs with mGluR5 negative modulators has demonstrated the potential clinical significance of this approach, and positive modulators or agonists at mGluR4 also look very promising. In this chapter we will review the development and current status of compounds that modulate iGluRs and mGluRs for the treatment of PD and illustrate the challenges and opportunities that these compounds present.

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