PACAP/VIP in the prefrontal cortex mediates the rapid antidepressant effects of zhizichi decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhizichi decoction (ZZCD) is a traditional Chinese medicine formula that consists of Gardenia jasminoides J.Ellis (GJ) and Semen Sojae Praeparatum. It is used to treat insomnia and emotion-related disorders, such as irritability. Previous studies have found that GJ has a rapid antidepressant effect. The study found that ZZCD is safer than GJ at the same dosage. Consequently, ZZCD is a superior drug with quicker antidepressant effects than GJ. The rapid antidepressant effects of ZZCD were examined in this study, along with the components that make up this effect. It was determined that the activation of prefrontal Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)/Vasoactive Intestinal Polypeptide (VIP) is essential for ZZCD's rapid antidepressant effects.

AIM: This study identified and discussed the rapid antidepressant effects and biological mechanisms of ZZCD.

MATERIALS AND METHODS: The tail suspension test (TST) and the forced swimming test (FST) were used to screen the effective dosage of ZZCD (0.67 g/kg, 1 g/kg, 4 g/kg). The effective dosage of ZZCD (1 g/kg) was tested in the TST conducted on Institute of Cancer Research (ICR) mice that were treated with lipopolysaccharide (LPS) at a concentration of 0.1 mg/mL. To confirm the expression of c-Fos, PACAP, and VIP in the prefrontal cortex (PFC), immunohistochemistry tests were conducted on mice following intragastric injection of ZZCD. Chemical characterization analysis and HPLC quality control analysis were conducted using UHPLC-Q-Obitrap-HRMS and chromatographic analysis.

RESULTS: The results showed that an acute administration of ZZCD (1 g/kg) decreased the immobility time of Kunming (KM) mice in TST and FST. Depressive behaviors in TST-induced ICR mice treated with LPS (0.1 mg/mL) were reversed by ZZCD (1 g/kg). The results of immunohistochemical experiments showed that ZZCD (1 g/kg) activated neurons in the PFC and PACAP/VIP in the PFC. In this study, 22 substances in ZZCD were identified. Five primary distinctive fingerprint peaks-geniposide, genistin, genipin-1-β-D-gentiobioside, glycitin, and daidzin-were found among the ten common peaks.

CONCLUSION: ZZCD (1 g/kg) had significant rapid antidepressant effects. PACAP/VIP in the PFC was found to mediate the rapid antidepressant effects of ZZCD.