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  • Ketamine has recently been found to


    Ketamine has recently been found to exert rapid and sustained antidepressant effect. Single dose ketamine can have an efficacy of up to 1 week [20]. Furthermore, ketamine is an effective drug against refractory depression [21,22]. The antidepressant mechanism of ketamine is still unclear. Whether CORT and GRs are involved in ketamine's antidepressant effects remain unclear, representing a key aspect of our study.
    Materials and methods
    Discussion Stressful events are an important factor for depression. However, only a portion of individuals develop into depression after stress events. Both clinical and animal studies focus on the mechanisms for susceptibility and resilience to stress [27]. The CSDS model is an ideal animal model to study depressive-like behaviors [23,28] which could distinguish susceptibility from resilience. Different responses of the HPA axis to stress may be the key to susceptibility and resistance. The hypothalamus secretes corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the pituitary system and causes the anterior lobe of the pituitary to secrete corticotropin hormone (ACTH). ACTH ultimately causes the adrenal gland to secrete Ozagrel HCl (in humans) and CORT (in rodents). CORT is a main stress hormone. Under normal circumstances, the HPA axis is regulated by negative feedback [29,30]. Impairment of this negative feedback leads to excessive CORT, which has been reported to be an important factor for depression [31,32]. Repeated exposure to stress usually elevates basal CORT levels [[33], [34], [35], [36]]. Our study found that the plasma CORT concentration was negatively correlated with the SI ratio after single social defeat stress. Furthermore, the plasma CORT concentration of these mice was still higher than those of the resilient and control mice 48 h after the last social defeat stress, suggesting that abnormal CORT was closely relevant to depressive susceptibility. MR and GR are two receptor subtypes for glucocorticoid involved in the regulation of circulating CORT. The MR has a ten-fold higher affinity to cortisol/corticosterone than the GR, resulting in an extensive activity of the MR under basal corticosteroid levels. Marked GR occupation occurs only at high corticosteroid concentrations, i.e., at the circadian peak of hormone secretion from the adrenal cortex or under stress. The GR is therefore believed to be more important in the regulation of the response to stress when endogenous levels of glucocorticoids are high [37]. While the MR plays an important role in the maintenance of basal CORT levels [38]. Chronic stress is known to increase sympathetic nervous system tone [39,40]. Previous studies have found the sympathetic nervous system innervates the adrenal cortex and influences plasma CORT production [41]. Stimulation of the splanchnic nerve, the branch of the sympathetic nervous system that innervates the adrenal, increases cortisol secretion in dogs which the pituitary is removed and replacement with constant ACTH [42]. Repeated stressor exposure results in increase of basal CORT in rats, but not ACTH levels. Administration of ganglion antagonists rather than inhibition of ACTH reduces the basal CORT levels in chronically stressed rats [43]. The increased sympathetic nervous system tone caused by chronic stress may be a potential mechanism for the increase of CORT level. Our study also found that the GR expression in the hippocampus of susceptible mice was decreased compared with resilient and control mice. This is in agreement with many other studies showing that chronic exposure to various stressors or glucocorticoid exposure can down-regulate GR mRNA and/or protein binding activity in this brain area [36,[44], [45], [46], [47], [48], [49], [50]]. Down-regulation of GR caused by chronic stress may last a long time. The GR mRNA was still lower than that in non-stress group at 48 h and 8 d after stress termination [46]. The decreased GR expression after chronic stress may be associated with transcriptional repression. High CORT concentrations following stress can mobilize a large number of GRs towards the negative glucocorticoid responsive elements found in the promoter region of GR gene [51]. Binding of activated GR complexes to these elements can repress transcription of the GR gene [52].