The Rapid Anti-PTSD Effects And Mechanisms Of YL-IPA08

Background:Post-traumatic stress disorder(PTSD)is the most common mental disorder among people who experienced sudden and disastrous events such as war and earthquake.Patients showed marked alterations in arousal and reactivity to the traumatic events.However,the mechanism of PTSD is far from clear and the only two FDA-approved pharmacological treatments for PTSD,paroxetine and sertraline,rarely produce a response rate exceeding 60%,and less than 30%of the patients achieve clinical remission.The two drugs both have defects such as low efficiency,slow onset,sexal dysfunction and gastrointestinal dysfunction.Therefore,it is of great significance to find new potential targets for anti-PTSD therapy and to develop new drugs.The present study used the time-dependent stress sensitization(TDS)method to establish a rat model of PTSD for the purpose of exploring the anti-PTSD effects and mechanisms of YL-IPA08,a newly developed TSPO ligands with potent antidepressant and anxiolytic effects.Methods:The time-dependent stress sensitization(TDS)method was used to establish a rat model of PTSD.The open field test(OFT)was used to evaluate the locomotor activity in rats.The contextual freezing(CF)measurement,elevated plus maze(EPM)test and novel objective recognition(NOR)test were used to evaluate the PTSD-like behaviors in rats.The concentration of allopregnanolone and corticosterone in rat hippocampus and cortex was detected by ELISA.The concentration of GABA in rat hippocampus and cortex was detected by HPLC-ECD.Results:PTSD rats showed significant PTSD-like behaviors with enhanced contexual freezing time in CF mearsurement,decreased open arm time and open arm entries in EPM test,and decreased object recognition index in NOR test(P<0.05 or 0.01).The levels of corticosterone was decreased in PTSD rats(P<0.05).Moreover,the concentration of hippocampus and cortex allopregnanolone was decreased in PTSD rats(P<0.05).YL-IPA08(0.05-0.lmg/kg)or positive drug sertraline(15mg/kg),administered intragastrically after establishment of PTSD model,significantly reversed these PTSD-like behavioral changes above(P<0.05 or 0.01),and increased the levels of serum corticosterone,andthe contentration of allopregnanolone and GABA in the hippocampus and cortex of PTSD rats.Conclusion:YL-IPA08 can improve the PTSD-like behaviors in rats,and its mechanisms may be related to increased allopregnanolone and GABA levels in hippocampus and cortex.Compared with the results of 4 days and 8 days,YL-IPA08 may have a faster and better anti-PTSD effect than the positive drug sertraline.