Ketamine improved depressive-like behaviors via hippocampal glucocorticoid receptor in chronic stress induced- susceptible mice

•Susceptible mice showed depressive-like behaviors upon chronic social defeat stress.•Plasma corticosterone concentration might predict susceptibility to chronic stress.•Abnormal glucocorticoid receptor expression was associated with susceptibility.•Ketamine exerted antidepressant effect via normalizing HPA axis response. Chronic stress is an important factor for depression. Most individuals recover from stress, while some develop into depression. The pathogenesis of resilience or susceptibility remains unclear. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and releases stress hormones to regulate individual response to stress. Hence, we assessed the effects of chronic social defeat stress (CSDS) on susceptible behaviors, plasma corticosterone (CORT) concentration, glucocorticoid receptor (GR) expressions in hippocampus and medial prefrontal cortex (mPFC). Mice that plasma CORT concentration is increased 2 h after single social defeat stress developed into susceptible mice after 10 d social defeat stress. The plasma CORT concentration was still higher than that of resilient mice 48 h after the last defeat stress. Mice administered CORT via drinking water showed susceptibility. Mifepristone, a GR antagonist improved susceptibility to chronic stress. Single dose ketamine treatment improved depressive-like behaviors, decreased plasma CORT concentration, rescued GR expression and nuclear translocation in the hippocampus of susceptible mice. These results suggested that abnormal CORT concentration after stress may predict susceptibility to depression in clinic. Ketamine may exert the antidepressant effect via normalizing HPA axis response and have significance in the clinic.