Schizandrin ameliorates post-traumatic stress disorder-like behaviors via 5-HT_1Areceptor in mice

Although selective serotonin reuptake inhibitors are the primary treatment for post-traumatic stress disorder (PTSD), they do not address all aspects of PTSD, highlighting the need for new therapies. Schizandrin, a lignan compound found in Schisandra chinensis, alleviates cognitive dysfunction, depression-like behaviors, and anxiety, suggesting that it may ameliorate PTSD symptoms. However, to date, no studies have explored the effects of schizandrin on PTSD symptoms. In the present study, we investigated whether schizandrin alleviates PTSD-like symptoms and explored its mechanism of action. We used a single prolonged stress (SPS) mouse model, a well-known animal model for simulating PTSD, to observe anti-PTSD activities. Behavioral experiments to evaluate emotional and cognitive impairments, network pharmacology, molecular docking analysis, and western blotting were performed. Schizandrin (10 mg/kg, p.o.) mitigated anxiety-like behavior as measured by the elevated plus-maze test, alleviated depression-like behavior as evaluated by the tail suspension test, and improved cognitive dysfunction as assessed by the Y-maze test. Furthermore, schizandrin reduced acquired fear memory in the SPS mouse model, as examined using the fear extinction test. Network pharmacology and molecular docking analyses revealed that schizandrin were bound most stably to the 5-HT_1Areceptor, a key modulator of fear and stress responses. Finally, we found that schizandrin activated 5-HT_1Areceptors and subsequently normalized the PI3K-Akt-mTOR and PKA-CREB signaling pathways in the amygdala of the SPS mouse model. These findings suggest that schizandrin is a potential therapeutic candidate for alleviating the multifaceted symptoms of PTSD.