Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects
| Autor: | Jan Kehr, Omid Miry, Patric K. Stanton, Amanda L. Gross, Joseph R. Moskal, Takashi Yoshitake, Xiao-Lei Zhang, Jeffery S. Burgdorf, Yong-Xin Li, Yuan Xing Guo, Roger A. Kroes, John E. Donello, Pradeep Banerjee |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Agonist endocrine system diseases medicine.drug_class Microdialysis Pharmacology Neurotransmission Regular Research Articles Receptors N-Methyl-D-Aspartate Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Postsynaptic potential Rapastinel medicine Animals Pharmacology (medical) Cells Cultured Cerebral Cortex Dose-Response Relationship Drug Chemistry nutritional and metabolic diseases Long-term potentiation NMDA receptor Antidepressive Agents Rats Drug Partial Agonism Psychiatry and Mental health Treatment Outcome 030104 developmental biology depression Synaptic plasticity Excitatory postsynaptic potential rapastinel Oligopeptides hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Neuropsychopharmacology |
| ISSN: | 1469-5111 1461-1457 |
| DOI: | 10.1093/ijnp/pyy101 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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