期刊
PSYCHOPHARMACOLOGY
卷 233, 期 19-20, 页码 3647-3657出版社
SPRINGER
DOI: 10.1007/s00213-016-4399-2
关键词
Antidepressant; Brain-derived neurotrophic factor; R-ketamine; Rapastinel; Synaptogenesis
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and development, AMED
- China Scholarship Council
- Japan Society for the Promotion of Science (JSPS) (Tokyo, Japan)
- JSPS (Tokyo, Japan)
- Nurture of Creative Research Leaders in Immune System Regulation and Innovative Therapeutics Program of Chiba University
- Grants-in-Aid for Scientific Research [24116006] Funding Source: KAKEN
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. We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model. 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 alpha-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. 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.
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