Research On The Function And Mechanism Of Ketamine Against Post-traumatic Stress Disorder

Studies have demonstrated that N-methyl-D-aspartate (NMDA)receptor antagonist ketamine displayed significant antianxiety andantidepressant-like effect. However, there has been no finding about itstherapeutic effects on post-traumatic stress disorder (PTSD). Therefore, theaim of the present research was to investigate whether ketamine possesanti-post-traumatic stress disorder effects in animal model and to explorethe relative mechanisms focusing on No signaling pathway neuroplasticityand neurogenesis, Ketamine can provide reliable experimental basis as aneffective drug prevention and treatment of PTSD. In this study, two animalmodels including the inescapable electric foot shocks in mice and thetime-deptendent sensitized stress (TDS) in rats were established to evaluateanti-PTSD effect of ketamine. The effects of ketamine on the spontaneousmotor activity in the animals were assessed using the open-field test.Frozen behavior test, plus maze test and staircase test were used to evaluatethe behavioral anti-PTSD effect of ketamine. Furthermore, the expressionof the BDNF、CREB、p-CREB、iNOS、nNOS in the hippocampus of theexperimental animals were detected by Western-blot analysis.(1) Datefrom the open field test depicted that chronic treatment with ketamine hadno effects on the locomotor activity in the shocked mice. Ketaminetreatment significantly decreased the frozen time of the PTSD-mice in thefrozen behavior test. Compared with the model group of mice, ketaminetreated mice showed significantly increased percentages of time spendingin the open arms and number of ingressing into the open arms in theelevated plus-mazed test. In the staircase test, there was no difference in the numbers of climbing in mice among all the groups. The mice in PTSDmodel group showed significantly increased number of rearing comparedwith mice in control group. Chronic administration of ketamine(0.625mg/kg,2.5mg/kg) significantly decreased the number of rearing inPTSD mice.(2)The chronic treatment with ketamine had no effects on thelocomotor activity in rats in the open field test. Ketamine(0.625mg/kg,2.5mg/kg) treatment significantly reversed the extension of frozen time inTDS rats in the frozen behavior test. In the elevated plus-mazed test,treatment with ketamine (2.5mg/kg) significantly increased the percentagesof time spending in the open arms and number of ingressing into the openarms in TDS-rats.(3) Western-blot analysis demonstrated that ketaminetreatment significantly increased the expression of p-CREB and BDNF anddecreased the expression of iNOS and nNOS in the hippocampal of PTSDmodel animals. The results suggest that ketamine display its anti-PTSDeffects on behavior manner in the two animal models of the preshock inmice and the TDS in rats. The underlying mechanisms may be related tothe neurogenesis improvement action and the inhibition of NO signalingpathway.