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  • Animal studies have shown that various antidepressant treatm

    2021-10-15

    Animal studies have shown that various antidepressant treatment are capable of upregulating GR protein and mRNA in key Concanamycin A regions including the hippocampus and decreasing basal and/or stress-induced glucocorticoid secretion [37]. Changes in the level or function of GR regulate the negative feedback of the HPA axis. Antidepressant treatment may directly induce GR upregulation, which in turn leads to enhanced response of the HPA axis to negative feedback of glucocorticoids and therefore to normalization of the HPA hyperactivity. An alternative interpretation is that antidepressants activate GR (nuclear translocation) and lead to resolution of glucocorticoid hypersecretion. Once prevailing glucocorticoids are reduced, GR upregulation can occur. In addition, the activated GR may itself induce increased GRs (autoinduction) [37]. After binding with GR, the CORT translocates into the nucleus to regulate gene expression. The persistent CORT and GR dysfunction may lead to the inhibition of neurogenesis [53,54], increased inflammatory responses [55], upregulated apoptosis [56,57], and decreased synaptic plasticity [58,59], which eventually cause depression. In view of the presence of excessive cortisol in depressed patients, studies have attempted to antagonize GRs using mifepristone to interfere the interaction between cortisol and GRs, thus inducing antidepressant effects [60]. GR antagonist Org 34850 can accelerate and enhance the antidepressant efficacy of fluoxetine [13]. Our results also revealed that the GR antagonist mifepristone protected mice from susceptible symptoms. However, Antidepressant sertraline can increase neurogenesis in the hippocampus, and this action can be counteracted by the GR antagonist mifepristone [15], which suggests the complexity of GRs in antidepressant mechanisms [61]. In recent years, ketamine, a noncompetitive NMDA receptor antagonist has been found to exert a rapid and sustained antidepressant effect, while AMPA receptor antagonist pretreatment can block the antidepressant effect of ketamine [[62], [63], [64]]. These suggest that NMDA/AMPA receptors may be involved in the antidepressant mechanism of ketamine via regulating HPA axis response to stress. For example, simultaneous blocking of NMDA and AMPA receptors inhibits ACTH release induced by foot shock stress [65]. Felbamate, an antiepileptic drug known to antagonizing NMDA receptor, can reduce CORT release induced by repeated stress of social defeat in mice [66]. NMDA receptor antagonist memantine reversed the increase of corticosterone levels induced by chronic stressful stimuli [67]. High-frequency bed nucleus of stria terminalis (BNST) stimulation produced long-lasting suppression of evoked field potentials recorded from the PVN, and this effect was blocked by administration of MK-801, suggesting NMDA receptor mediates regulation of the HPA axis [68]. Animal experiments have revealed that long-term antidepressant treatment increases the expression and function of GRs and MRs [69,70], which may improve the negative feedback of the HPA axis. The present study showed that single dose intraperitoneal injection of ketamine increased GR expression in the hippocampus, decreased plasma CORT concentration and improved depression symptoms. Ketamine is an anesthetic used clinically for sedation, analgesia, and anesthesia [71]. To our knowledge, this is the first report that ketamine increased the expression of GR in the hippocampus of susceptible mice after CSDS, downregulated plasma CORT concentration and improved depressive behaviors. However, ketamine has some drawbacks, including its psychotic-like side effects and addictiveness, which limit its clinical use [72,73]. Recent studies have found that ketamine metabolites, such as (2R, 6R)-hydroxynorketamine (HNK), exert ketamine-like antidepressant effects without the related side effects of ketamine [20,74]. But whether (2R,6R)-HNK can also regulate HPA function requires further study.
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