Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression

Abstract

RationaleThe N-methyl-d-aspartate (NMDA) receptor antagonists, including R-ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression.ObjectiveWe compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model.ResultsIn the tail suspension and forced swimming tests, R-ketamine (10 mg/kg, intraperitoneal (i.p.)) or rapastinel (10 mg/kg, i.p.) significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, both compounds significantly enhanced the reduced preference in susceptible mice 2, 4, or 7 days after a single injection. All mice were sacrificed 8 days after a single injection. Western blot analyses showed that R-ketamine, but not rapastinel, significantly attenuated the reduced brain-derived neurotrophic factor (BDNF)-TrkB signaling, postsynaptic density protein 95 (PSD-95), and GluA1 (a subtype of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor) in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus in the susceptible mice. In contrast, both compounds had no effect against the increased BDNF-TrkB signaling, PSD-95, and GluA1 seen in the nucleus accumbens of susceptible mice. Moreover, sustained antidepressant effect of R-ketamine (3 mg/kg, intravenous (i.v.)), but not rapastinel (3 mg/kg, i.v.), was detected 7 days after a single dose.ConclusionsThese results highlight R-ketamine as a longer lasting antidepressant compared with rapastinel in social defeat stress model. It is likely that synaptogenesis including BDNF-TrkB signaling in the prefrontal cortex (PFC) and hippocampus may be required for the mechanisms promoting this sustained antidepressant effect.

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…Indeed, in this study, we did not correlate our electrophysiological observations with behavioral alterations induced by ketamine or (2R,6R)-HNK, because the latter have been described in several other published studies and the doses used are well described for producing antidepressant actions in rodent models. 6,19,85 The role of ionotropic glutamate receptors in the NAc and VTA, and the involvement of these brain regions in mediating the effects of ketamine have not been extensively examined. To better disentangle the role of the AMPARs and NMDARs in the VTA-NAc circuit in the therapeutic versus side effects of ketamine, future electrophysiological and behavioral studies with, for example, conditional mice with ablation of specific AMPAR or NMDAR subunits in the VTA and NAc are needed.…”

Mechanisms of ketamine action as an antidepressant

“…Another finding challenging the NMDAR inhibition hypothesis of ketamine’s antidepressant mechanism of action is the fact that partial agonists at the NMDAR glycine B binding site, including GLYX-13 (i.e., rapastinel) and D-cycloserine manifest antidepressant effects in clinical trials 104, 105 and in animal tests 106–109 , without sharing ketamine’s NMDAR inhibition-mediated side effects 109 . Furthermore, in vivo evidence shows that GLYX-13 is able to reduce ketamine-induced memory deficits in mice 110 , which are NMDAR inhibition-mediated.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…The clinical findings regarding ketamine’s antidepressant actions are also supported by animal tests that predict rapid-onset antidepressant action, including the 24-h forced-swim test [42–44], learned helplessness [42, 43, 45–51], novelty-suppressed feeding [49, 52–55], and novelty-induced hypophagia [56, 57]. Ketamine also reverses anhedonia and other maladaptive behaviors following chronic mild stress [43, 55] and chronic social defeat stress [45, 58–61]; also see Table 1. Only few animal studies have been published to date assessing the effects of ketamine on endophenotypes of suicidal behavior (as discussed in [62]).…”

“…Moreover, a single administration of GLYX-13 induces rapid and sustained antidepressant actions in several animal tests, including the 24-h forced-swim test [57, 128], learned helplessness [57], novelty-suppressed feeding [128], novelty-induced hypophagia [57], and female urine sniffing test [128]. Moreover, it reversed anhedonia and other maladaptive behaviors following chronic mild stress [57] and chronic social defeat stress [58] (see Table 1). …”