Research On The Effect And Mechanism Of S-ketamine Against Post-traumatic Stress Disorder

Objective:Post-traumatic stress disorder(PTSD)is a chronic and severe psychiatric disorder with intrusive re-experience of the traumatic event,persistent avoidance behavior,and intense psychological distress to cues.Due to its unclear pharmacological mechanism,the current therapeutic agents have proven to be less effective.S-ketamine is a non-competitive N-methyl-D-Aspartate receptors(NMDARs)antagonist.Recently,S-ketamine was approved by the Food and Drug Administration(FDA)for treatment resistant depression(TRD),which has a greater affinity with NMDAR than their Renantiomers.However,its pharmacological mechanism is unclear.We wondered if Sketamine had the same therapeutic effect on PTSD.Based on this hypothesis,our study applied the behavioral test,transmission electron microscope and molecular biological methods to explore the novel pathophysiological mechanism of PTSD and possible therapeutic mechanism of S-ketamine on PTSD.Methods:C57BL/6 male mice weighting 25g-30g were randomly divided into 4 groups:the control group(CON+NS group),the control administration group(CON+SK group),the PTSD group(PTSD+NS group),and the PTSD administration group(PTSD+SK group).Inescapable foot shock(IFS)procedure was used to establish an animal model of PTSD.The CON+SK group and the PTSD+SK group were administered with S-ketamine(3mg/kg)intraperitoneally once a day for 14 consecutive days starting from the day of model finishing.In the meantime,the CON+NS group and the PTSD+NS group were treated with the same volume of saline.Stress-related behavioral changes were evaluated by fear condition(FC),open-field test(OFT),and elevated plus maze test(EPMT).The expressions of P-CREB,TrkB,P-TrkB,BDNF,GluR1,GluR2,GluN2A,GluN2B in the hippocampus were detected by western blot.The level of BDNF in the regions of hippocampus was tested by immunofluorescence staining.In addition,the ultrastructure of synapses in were also measured by transmission electron microscope.Results:In the FC test,compared with the CON+NS group,mice in the PTSD+NS group showed increases in freezing time,fecal production,and a decrease in spontaneous locomotion.In the OFT,the entries to the central area in the PTSD+NS group were less than those in the CON+NS group.There was no significant difference in the total distance traveled among all groups.In the EPMT,mice in the PTSD+NS group showed significant reductions in the time spent in open arms and number of entries into open arms compared with those in the Con+NS group.The repeated administration of S-ketamine significantly prevented these changes.Compared with the CON+NS group,mice in the PTSD+NS group showed increases in the protein levels of GluRl,GluN2B and decreases in the protein levels of P-CREB,P-TrkB,BDNF and the ratio of P-TrkB/TrkB.The repeated administration of S-ketamine significantly inhibited these changes.Consistent with the result of western blot,the fluorescence intensity of BDNF markedly decreased in PTSD+NS group and significantly increased after repeated administration of S-ketamine.The result of ultrastructural of synapses showed that the synaptic cleft width was significantly wider in the PTSD+NS group than those in the CON+NS group.The width decreased significantly after S-ketamine treatment.By contrast,the mean PSD thickness and max PSD thickness decreased in the PTSD+NS group relative to those in the CON+NS group and increased significantly in the PTSD+SK group after S-ketamine administration.In addition,the results showed that IFS or S-ketamine exerted no significant effects on the synaptic interface curvature.Conclusion:The PTSD mice modeled with IFS showed increased fear memory and anxiety-like behavior.S-ketamine could generally exert a therapeutic effect on PTSD,which could be related to the alterations in synaptic morphology and function in the GluN2B/CREB/BDNF pathway.