Previous studies reported that ginsenoside Rg1 (Rg1) exerts antidepressant-like effect in animal models of depression. However, its effect on post-traumatic stress disorder (PTSD) remains elusive; PTSD is a common and costly psychiatric condition with negative cognitive and affective dysfunctions, such as anxiety and depression. In this study, we evaluated the role of Rg1 in a validated mice model of PTSD induced by single-prolonged stress (SPS). Sertraline, one of the FDA-approved medications for PTSD was used as a positive control. Our results showed that SPS exposure led to increased anxiety-like and despair-like behaviors. SPS exposure also caused enhanced contextual fear memory and overgeneralization of learned fear. Sertraline significantly ameliorated those abnormal behaviors induced by SPS, while Rg1 did not. Meanwhile, we found that sertraline but not Rg1 blocked the suppressive effect of SPS on adult neurogenesis in the hippocampus. Consistently, we found that SPS elevated adrenocorticotropic hormone (ACTH) level in the serum, which was inhibited by sertraline but not Rg1. Our results thus demonstrate that Rg1 at a dose used to treat depression may not be effective to rescue behavioral deficits associated with PTSD. (C) 2020 Elsevier Inc. All rights reserved.