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

Abstract

Rationale: The N-methyl-D-aspartate (NMDA) receptor antagonists, including R-ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression.

Objective: We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model.

Results: In 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.

Conclusions: These 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.

Keywords: Antidepressant; Brain-derived neurotrophic factor; R-ketamine; Rapastinel; Synaptogenesis.

Fig. 1

The schedule of social defeat stress, drug administration, behavioral tests, and brain sampling. a Repeated social defeat stress was performed for 10 days (day 1–day 10). Social interaction test was performed on day 11, and susceptible mice were used in the subsequent experiments. Vehicle (10 ml/kg, i.p.), R-ketamine (10 mg/kg, i.p.), or rapastinel (10 mg/kg, i.p.) was administered (day 12). Locomotion test (LMT) and tail suspension test (TST) were performed 2 and 4 h after a single injection, respectively (day 12). Forced swimming test (FST) was performed 1 day after injection (day 13). One percent sucrose preference test (SPT) was performed 2 days (day 14), 4 days (day 15), and 7 days (day 19) after injection. Collection of brain regions was performed at day 20. b Repeated social defeat stress was performed for 10 days (day 1–day 10). Social interaction test was performed on day 11, and susceptible mice were used in the subsequent experiments. Vehicle (5 ml/kg, i.v.), R-ketamine (3 mg/kg, i.v.), or rapastinel (3 mg/kg, i.v.) was administered (day 12). LMT and TST were performed 2 and 4 h after a single injection, respectively, (day 12). FST was performed 1 day after injection (day 13). One percent SPT was performed 2 days (day 14), 4 days (day 15), and 7 days (day 19) after a single injection

Fig. 2

Effects of i.p. administration of R-ketamine and rapastinel in social defeat stress model. a LMT (day 12), b TST (day 12), c FST (day 13), d SPT (day 14), e SPT (day 16), and f SPT (day 19). The values represent the mean ± SEM (n = 9 or 10). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the vehicle-treated stress group. ^# P < 0.05, ^## P < 0.01 compared with R-ketamine treated stress group. N.S. not significant, Con control, Veh vehicle, R-Ket R-ketamine, Rap rapastinel, LMT locomotion test, TST tail suspension test, FST forced swimming test, SPT 1 % sucrose preference test

Fig. 3

Levels of proBDNF and BDNF in the brain regions. a Western blot analysis of proBDNF in PFC, NAc, CA1, CA3, and DG of the hippocampus. The value was expressed as a percentage of that of control mice. The values represent the mean ± SEM (n = 6 or 7). N.S. not significant. b Western blot analysis of BDNF (mature form) in PFC, NAc, CA1, CA3, and DG of the hippocampus. The value was expressed as a percentage of that of control mice. The values represent the mean ± SEM (n = 6 or 7). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the vehicle-treated stress group. ^# P < 0.05, ^## P < 0.01 compared with R-ketamine treated stress group. N.S. not significant. Con control, Veh vehicle, R-Ket R-ketamine, Rap rapastinel

Fig. 4

The ratio of p-TrkB/TrkB in the brain regions. a Western blot analysis of TrkB and p-TrkB proteins in PFC, NAc, CA1, CA3, and DG of the hippocampus. The value of p-TrkB/TrkB ratio was expressed as a percentage of that of control mice. The values represent the mean± SEM (n = 6 or 7). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the vehicle-treated stress group. ^# P < 0.05, ^## P < 0.01 compared with R-ketamine treated stress group. N.S. not significant. b The value of total TrkB protein was expressed as a percentage of that of control mice. Values represent the mean ± SEM (n = 6 or 7). N.S. not significant, Con control, Veh vehicle, R-Ket R-ketamine, Rap rapastinel

Fig. 5

Levels of GluA1 and PSD-95 in the brain regions. a Western blot analysis of GluA1 in PFC, NAc, CA1, CA3, and DG of the hippocampus. The value was expressed as a percentage of that of control mice. Values represent the mean ± SEM (n = 6 or 7). *P < 0.05, **P < 0.01 compared with the vehicle-treated stress group. N.S. not significant. b Western blot analysis of PSD-95 in PFC, NAc, CA1, CA3, and DG of the hippocampus. The value was expressed as a percentage of that of control mice. Values represent the mean ± SEM (n = 6 or 7). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the vehicle + stress group. ^# P < 0.05, ^## P < 0.01 compared with R-ketamine treated stress group. N.S. not significant, Con control, Veh vehicle, R-Ket R-ketamine, Rap rapastinel

Fig. 6

Effects of i.v. administration of R-ketamine and rapastinel in social defeat stress model. a LMT (day 12), b TST (day 12), c FST (day 13), d SPT (day 14), e SPT (day 16), and f SPT (day 19). The values represent the mean ± SEM (n = 9). *P < 0.05, **P < 0.01, ***P < 0.001 compared with the vehicle-treated stress group. ^# P < 0.05 compared with R-ketamine treated stress group. N.S. not significant, Con control, Veh vehicle, R-Ket R-ketamine, Rap rapastinel, LMT locomotion test, TST tail suspension test, FST forced swimming test, SPT 1 % sucrose preference test