glyx-13-peptide and Depressive-Disorder

Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Contextual fear extinction (CFE) in rodents has been well characterized and used extensively as a model to study the neurobiological mechanisms of post-traumatic stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, studies were undertaken to examine the effects of rapastinel for its therapeutic potential in PTSD and to use rapastinel as a tool to study its underlying glutamatergic mechanisms. A 21-day chronic mild unpredictable stress (CUS) rat model was used to model depression and PTSD. The effects of CUS alone compared to No CUS controls, and the effects of rapastinel (3 mg/kg IV) on CUS-treated animals were examined. The effect of rapastinel was first assessed using CUS-treated rats in three depression models, Porsolt, sucrose preference, and novelty-induced hypophagia tests, and found to produce a complete reversal of the depressive-like state in each model. Rapastinel was then assessed in a MPFC-dependent positive emotional learning paradigm and in CFE and again a reversal of the impairments induced by CUS treatment was observed. Both synaptic plasticity and metaplasticity, as measured by the induction of long-term potentiation in rat MPFC slice preparations, was found to be markedly impaired in CUS-treated animals. This impairment was reversed when CUS-treated rats were administered rapastinel and tested 24 h later. Transcriptomic analysis of MPFC mRNA expression in CUS-treated rats corroborated the link between rapastinel's behavioral effects and synaptic plasticity. A marked enrichment in both the LTP and LTD connectomes in rapastinel-treated CUS rats was observed compared to CUS-treated controls. The effects of rapastinel on depression models, PEL, and most importantly on CFE demonstrate the therapeutic potential of rapastinel for the treatment of PTSD. Moreover, rapastinel appears to elicit its therapeutic effects through a NMDA receptor-mediated, LTP-like, metaplasticity process in the MPFC.

Topics: Animals; Chronic Disease; Depressive Disorder; Disease Models, Animal; Excitatory Amino Acid Agents; Learning; Long-Term Potentiation; Male; Memory; Oligopeptides; Prefrontal Cortex; Psychotropic Drugs; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stress Disorders, Post-Traumatic; Stress, Psychological; Tissue Culture Techniques; Transcriptome; Uncertainty

Rapastinel (GLYX-13) is an N-methyl-d-aspartate receptor (NMDAR) modulator that has characteristics of a glycine site partial agonist. Rapastinel is a robust cognitive enhancer and facilitates hippocampal long-term potentiation (LTP) of synaptic transmission in slices. In human clinical trials, rapastinel has been shown to produce marked antidepressant properties that last for at least one week following a single dose. The long-lasting antidepressant effect of a single dose of rapastinel (3mg/kg IV) was assessed in rats using the Porsolt, open field and ultrasonic vocalization assays. Cognitive enhancement was examined using the Morris water maze, positive emotional learning, and contextual fear extinction tests. LTP was assessed in hippocampal slices. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex. Significant antidepressant-like or cognitive enhancing effects were observed that lasted for at least one week in each model. Rapastinel facilitated LTP 1day-2weeks but not 4weeks post-dosing. Biweekly dosing with rapastinel sustained this effect for at least 8weeks. A single dose of rapastinel increased the proportion of whole-cell NMDAR current contributed by NR2B-containing NMDARs in the hippocampus 1week post-dosing, that returned to baseline by 4weeks post-dosing. The NMDAR antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the antidepressant-like effect of rapastinel 1week post dosing. A single injection of rapastinel also increased mature spine density in both brain regions 24h post-dosing. These data demonstrate that rapastinel produces its long-lasting antidepressant effects via triggering NMDAR-dependent processes that lead to increased sensitivity to LTP that persist for up to two weeks. These data also suggest that these processes led to the alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity associated with learning and memory.

Topics: Animals; Antidepressive Agents; Dendritic Spines; Depressive Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Maze Learning; Membrane Potentials; Memory; Neuronal Plasticity; Oligopeptides; Prefrontal Cortex; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Time Factors; Tissue Culture Techniques