Glycine site agonists of the N-methyl-D-aspartate receptor and Parkinson's disease: a hypothesis.

Limitations of current pharmacological approaches to Parkinson's disease (PD) highlight the need for the development of nondopaminergic therapeutic strategies. The potential role of glutamatergic neurotransmission modulators, including those active at the N-methyl-D-aspartate receptor (NMDAR), is presently under investigation. Most literature proposes the use of NMDAR antagonists based on neurodegenerative theories of NMDAR function. Nevertheless, NMDAR antagonism has proven disappointing in clinical trials and may be associated with serious adverse events. More recent theories indicate that NMDAR target selectivity may be a cardinal prerequisite for efficacy, with present efforts being devoted primarily to development of NMDAR-NR2B subunit antagonists. We propose a novel hypothesis according to which NMDAR stimulation, accomplished through allosteric modulation via the glycine modulatory site, may be beneficial in late-phase PD. This hypothesis stems from: (1) meta-analysis of randomized controlled trials performed in schizophrenia, indicating that glycine site agonists (eg, glycine, D-serine) alleviate antipsychotic-induced parkinsonian symptoms; (2) clinical observations indicating that NMDAR hypofunction is associated with motor disturbances; (3) results of a preliminary D-serine trial in PD; (4) data indicating glycine efficacy in a rat tardive dyskinesia model; and (5) no evidence of excitotoxic damage following chronic high-dose glycine nutritional supplementation. This hypothesis is discussed in the context of glycine site agonist effects on intrasynaptic NMDAR subunits and striatal synaptic plasticity.