Atractylenolide I improves behaviors in mice with depression‐like phenotype by modulating neurotransmitter balance via 5‐HT2A

Abstract To explore the antidepressant effects and targets of atractylenolide I (ATR) through a network pharmacological approach. Relevant targets of ATR and depression analyzed by network pharmacology were scored (identifying 5‐HT2A targets). Through elevated plus maze, open field, tail suspension, and forced swimming tests, the behavioral changes of mice with depression (chronic unpredictable mild stress [CUMS]) were examined, and the levels of neurotransmitters including serotonin, dopamine, and norepinephrine (5‐HT, DA, and NE) were determined. The binding of ATR to 5‐HT2A was verified by small molecular‐protein docking. ATR improved the behaviors of CUMS mice, elevated their levels of neurotransmitters 5‐HT, DA, and NE, and exerted a protective effect on their nerve cell injury. After 5‐HT2A knockout, ATR failed to further improve the CUMS behaviors. According to the results of small molecular‐protein docking and network pharmacological analysis, ATR acted as an inhibitor by binding to 5‐HT2A. ATR can improve the behaviors and modulate the neurotransmitters of CUMS mice by targeting 5‐HT2A.