Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression
Bangkun Yang, Ji-Chun Zhang, Mei Han, Wei Yao, Chun Yang, Qian Ren, Min Ma, Qianxue Chen, Kenji Hashimoto
Psychopharmacology August 3, 2016 DOI: 10.1007/s00213-016-4399-2 via OpenAlex
Summary
R-ketamine and rapastinel, both NMDA receptor antagonists, produced rapid antidepressant effects in mice susceptible to social defeat stress. A single injection of either compound (10 mg/kg) reduced immobility in the tail suspension and forced swimming tests and increased sucrose preference for up to seven days. R-ketamine, but not rapastinel, restored reduced BDNF-TrkB signaling, PSD-95, and GluA1 levels in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus. Neither compound altered the elevated levels of these proteins in the nucleus accumbens. A lower intravenous dose of R-ketamine (3 mg/kg) maintained antidepressant effects after seven days, whereas rapastinel did not, indicating R-ketamine produces a longer-lasting antidepressant effect.
Study at a glance
| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Susceptible mice in the social defeat stress model |
| Interventions | R-ketamine rapastinel |
| Dose | 10 mg/kg (intraperitoneal); 3 mg/kg (intravenous) |
| Duration | 8 days after a single injection |
| Topics | Ketamine |
| Keywords | Social defeat Behavioural despair test Nmda receptor Dentate gyrus |
| Citations | 93 |
| Key finding | R-ketamine produces a longer lasting antidepressant effect than rapastinel in the social defeat stress model, likely through restoration of BDNF-TrkB signaling and synaptic proteins in the prefrontal cortex and hippocampus. |
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.