Ketamine Improved Depressive-like Behaviors In Chronic Stress-susceptible Mice Via Hippocampal Glucocorticoid Receptor

Objective Chronic social defeat stress resulted in different behaviors in mice-stress susceptible subgroup and stress resistance subgroup.This study explored the correlation between stress susceptibility and plasma corticosterone levels.Ketamine antidepressant mechanism by regulated of Glucocorticoid Receptors(GR)Expression in the Hippocampus and corticosterone(CORT)levels in plasma.Sought new strategies for the treatment of depression.Methods 1.To explore the correlation between stress susceptibility and plasma corticosterone levels in mice with chronic social defeat stress.C57 mice were randomly divided into control group(CON)and social defeat model group(SD).In the SD group,blood was collected 2 h after a single social defeat stress,and the CON group mice were collected blood samples at the same time.After 7 days of recovery,the social defeat stress model and social tests were used to divide SD mice into stress susceptible(SUS)and stress resiliently(RES)groups.The Sucrose preference test measures depression-like behavior in mice.The blood sample was taken again 48 hours after the last social defeat stress.The enzyme-Linked Immuno Sorbent Assay(ELISA)was used to detect the differences in plasma corticosterone levels between the groups.To exclude possible differences in activity in mice,mice activity was measured after social defeat stress.2.Corticosterone promotes stress susceptibility in mice.C57 mice were randomly divided into 4 groups: control group(CON),social defeat stress group(MSD),corticosterone group(CORT),corticosterone combined with social defeat stress(CORT+MSD).The CORT group and CORT+MSD group were given drinking water containing CORT for 14 days,and the SD group and CORT+MSD group were given social defeat stress on the 15 th day,each time for 5 minutes with an interval of 30 minutes for 3 times.Social interaction test conducted on the 16 th day.In order to exclude the possible anxiety induced by corticosterone,the open field test and elevated plus maze test were used to detect the anxiety behavior of mice.3.The Protective Effect of glucocorticoid receptor antagonist mifepristoneon Chronic Social defeat Stress.C57 mice were randomly divided into 3 groups: control group(CON),socially defeat mice given mifepristone treatment group(M),and social defeat stress mice given solvent control group(NS).Mifepristone was is administered 30 minutes before each the social defeat stress in SD+M mice.For 10 consecutive days,NS group was given intraperitoneal injection of saline.Social testing on day 11.To exclude possible differences in activity in mice,mice activity was measured after social defeat stress.4.Antidepressant effect of Ketamine on susceptible mice with chronic social defeat Stress.C57 mice were randomly divided into control group(CON)and chronic social defeat stress group(SD).SD group was divided into stress-susceptible(SUS)and stress resilient(RES)phenotypes by social interaction test.The susceptible mice were treated with ketamine or saline respectively.Behavioral tests include sucrose preference test,and forced swim test.The expression of GR and mineralocorticoid receptor(MR)in hippocampus and prefrontal cortex of mice were detected by Western blotting.The level of acetylation of histone H3 and H4 and the expression of histone deacetylase HDAC2,HDAC3,HDAC4 and HDAC6 were detected by immunoblotting.The plasma corticosterone levels were measured by ELISA.Results 1.The plasma CORT level in part of mice was continuously increased at 2 h after a single social defeat stress.The social ratio of these mice was less than 1 in the subsequent social tests,which showed the susceptibility to stress.The plasma CORT level was negatively correlated with the social ratio.Sucrose preference of susceptible mice was decreased compared with the resilient group and the control group,showing depression-like behavior.The level of plasma CORT of susceptible mice was still higher than that in CON and RES groups at 48 h after the last stress.2.After 14 days of exogenous CORT drinking,mice in the CORT+MSD group showed social avoidance with social interaction test.The social ratio was less than 1 and the mice was Stress susceptible.There was no difference in the total movement distance,the number of total crossing line times in open field test.There was no difference in stay time in the central area and the stay time/total time of open arms in each group of mice in the elevated plus maze test.3.Glucocorticoid receptor antagonist Mifepristone was more effective than normal saline(NS)in intraperitoneal injection 30 minutes before the social defeat stress to protect mice from stress susceptible.There was no difference in the activity of mice in each group.4.Ketamine Treatment increased Sucrose preference and reduced the immobility time of the forced swimming test in stress susceptible mice,and had no effect on the activity of mice.Ketamine treatment increased the expression of GR in the hippocampus of susceptible mice,and there was no difference in the expression of GR in them PFC of each group of mice.There was no difference in the expression of MR between the hippocampus and mPFC in each group.The levels of acetylation of H3 and H4 in hippocampus and the histone deacetylases HDAC2,HDAC3,HDAC4 and HDAC6 were not changed in each group.Conclusion1.Stress susceptibility to chronic social defeat in C57 mice was positively correlated with plasma CORT levels.Plasma CORT can be used as a predictor of stress susceptibility.2.Ketamine treatment increased the expression of GR in the hippocampus of susceptible mice,reduced plasma CORT levels,and improved depression-like behavior in stress susceptible mice.