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The total saponin from leaves of Panax notoginseng (Burk.) F.H.Chen (SLPN) is recorded in China Pharmacopoeia, whichis the main component of the traditional Chinese patent medicine "Qi Ye ShenAntablet" , used for the treatment of insomnia, anxiety and neurasthenia neurosis.Interestingly, our previous studies have firstly demonstrated SLPN.possessed strong antidepressant-like effects in several behavioral tests both in mice and rats.In the present study, we further investigated the detailed molecular mechanisms of SLPN' s antidepressant effects by using a chronic unpredictable mild stress (CUMS) rat model of depression.The present result showed 5 week chronic treatment with SLPN (70 and 100 mg/kg) and fluoxetine (10 mg/kg) could effectively reversed the CUMS-induced behavioral changes, such as the sucrose preference, the locomotor activity, the body weight, and the hippocampus percentage.Furthermore, our results demonstrated, unlike the positive control fluoxetine, SLPNsignificantly increased the noradrenaline (NA) and dopamine (DA) levels in the hippocampus, but it did not affect the serotonin (5-HT) levels.More importantly, immunohistochemistry results provided evidence that SLPN significantly reversed the decrease of some neurotrophic factor expressions in the hippocampus produced by CUMS, including the brain-derived neurotrophic factor (BDNF), the BDNFreceptor tropomyosin-related kinase B (TrkB), the phosphorylated cAMP response element-binding protein (p-CREB), and the phosphorylated extra-cellular signal-regulated kinase 1 and 2 (p-ERK1/2).Taken together, it is reasonable to speculate that SLPN exhibits antidepressant-like properties, which might be mediated through up-regulation of the hippocampal noradrenergic and dopaminergic levels, as well as the ERK1/2, CREB, and BDNF signalling pathways.