Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects

Authors

John Donello
Pradeep Banerjee
Yong-Xin Li
Yuan-Xing Guo
Takashi Yoshitake
Xiao-Lei Zhang, New York Medical CollegeFollow
Omid Miry
Jan Kehr
Patric K. Stanton, New York Medical CollegeFollow
Amanda L. Gross
Jeffery S. Burgdorf
Roger A. Kroes
Joseph R. Moskal

DOI

10.1093/ijnp/pyy101

Journal Title

The International Journal of Neuropsychopharmacology

First Page

247

Last Page

259

Document Type

Article

Publication Date

March 2019

Department

Cell Biology and Anatomy

Keywords

NMDA receptor, depression, rapastinel

Disciplines

Medicine and Health Sciences

Abstract

BACKGROUND: Modulation of glutamatergic synaptic transmission by N-methyl-D-aspartate receptors can produce rapid and sustained antidepressant effects. Rapastinel (GLYX-13), initially described as a N-methyl-D-aspartate receptor partial glycine site agonist, exhibits rapid antidepressant effect in rodents without the accompanying dissociative effects of N-methyl-D-aspartate receptor antagonists. METHODS: The relationship between rapastinel's in vitro N-methyl-D-aspartate receptor pharmacology and antidepressant efficacy was determined by brain microdialysis and subsequent pharmacological characterization of therapeutic rapastinel concentrations in N-methyl-D-aspartate receptor-specific radioligand displacement, calcium mobilization, and medial prefrontal cortex electrophysiology assays. RESULTS: Brain rapastinel concentrations of 30 to 100 nM were associated with its antidepressant-like efficacy and enhancement of N-methyl-D-aspartate receptor-dependent neuronal intracellular calcium mobilization. Modulation of N-methyl-D-aspartate receptors by rapastinel was independent of D-serine concentrations, and glycine site antagonists did not block rapastinel's effect. In rat medial prefrontal cortex slices, 100 nM rapastinel increased N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents and enhanced the magnitude of long-term potentiation without any effect on miniature EPSCs or paired-pulse facilitation responses, indicating postsynaptic action of rapastinel. A critical amino acid within the NR2 subunit was identified as necessary for rapastinel's modulatory effect. CONCLUSION: Rapastinel brain concentrations associated with antidepressant-like activity directly enhance medial prefrontal cortex N-methyl-D-aspartate receptor activity and N-methyl-D-aspartate receptor-mediated synaptic plasticity in vitro. At therapeutic concentrations, rapastinel directly enhances N-methyl-D-aspartate receptor activity through a novel site independent of the glycine coagonist site. While both rapastinel and ketamine physically target N-methyl-D-aspartate receptors, the 2 molecules have opposing actions on N-methyl-D-aspartate receptors. Modest positive modulation of N-methyl-D-aspartate receptors by rapastinel represents a novel pharmacological approach to promote well-tolerated, rapid, and sustained improvements in mood disorders.

Recommended Citation

Donello, J., Banerjee, P., Li, Y., Guo, Y., Yoshitake, T., Zhang, X., Miry, O., Kehr, J., Stanton, P., Gross, A., Burgdorf, J., Kroes, R., & Moskal, J. (2019). Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects. The International Journal of Neuropsychopharmacology, 22 (3), 247-259. https://doi.org/10.1093/ijnp/pyy101