Objective:Post-traumatic stress disorder(PTSD)is a psychiatric disorder characterized by depression and anxiety,that arises due to an imbalance of neurotransmitters in response to excessive stress.Hesperidin(HSD)is a naturally occurring flavonoid shown to exert a variety of biological activities,including antioxidant,anti-inflammatory,and neuroprotective effects.Methods:This study was used the open field test(OFT)and forced swimming test(FST)to examine the effects of HSD on the depression-like response of rats after exposure to a single prolonged stress(SPS)leading to the dysregulation of the serotonergic activation system.Male rats were given HSD(20,50,and 100 mg/kg,intraperitoneal injection,n=6-7 per group)once daily for 14 days after exposure to SPS.The influence of administration of HSD on SPS-induced behavioral responses and concentrations of serotonin(5-HT),5-hydroxyindoleacetic acid(5-HIAA),and monoamine oxidase-A(MAO-A)in the rat brain were also investigated using enzyme-linked immunoassays(ELISAs).Results:Daily HSD administration significantly improved depression-like behaviors in the FST(P＜0.05),increased the number of lines crossed in the central zone of the OFT(P＜0.01),and reduced freezing behavior both in contextual and cued fear conditioning.HSD treatment also attenuated the reduction in SPS-induced 5-HT concentrations in the hippocampus and amygdala.This increase in 5-HT concentrations during HSD treatment was partially attributed to a decrease in the 5-HIAA/5-HT ratio in the hippocampus of rats with PTSD.Furthermore,HSD treatment inhibited activity of MAO-A and decreases of tryptophan hydroxylase-1 expression in the hippocampus.Conclusion:HSD was shown to exert antidepressant effects in rats exposed to SPS,suggesting that this natural flavonoid may be an effective medicine for PTSD.