Glutamate modulation for the treatment of levodopa induced dyskinesia: a brief review of the drugs tested in the clinic.

Levodopa is the standard treatment for Parkinson's disease, but its use is marred by the emergence of dyskinesia, for which treatment options remain limited. Here, we review the glutamatergic modulators that were assessed for their antidyskinetic potential in clinical trials, including N-methyl-D-aspartate (NMDA) antagonists, agonists at the glycine-binding site on NMDA receptors, metabotropic glutamate (mGlu) 4 agonists, mGlu5 antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists and glutamate release inhibitors. Several agents that were investigated are not selective for their targets, raising uncertainty about the extent to which glutamatergic modulation contributed to their effects. Except for amantadine, the use of glutamatergic modulators for the treatment of dyskinesia in Parkinson's disease remains largely investigational, with promising results obtained with mGlu5 negative allosteric modulation.