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Objectives: Xiaochaihutang (XCHT) has been used in China for thousands of years to treat 'Shaoyang syndrome', which involves depressive-like symptoms. However, no studies were conducted to demonstrate its antidepressant effect and mechanism. This study was designed to confirm the antidepressant effect of XCHT and explore its mechanism using the pharmacological methods., Methods: Ultra-HPLC and mass spectrometry was used to identify the chemical constituents of XCHT. Forced swimming test (FST) and tail suspension test (TST) were used to determine the antidepressant-like activity of XCHT in mice and rats. The possible mechanism of XCHT was elucidated by the reserpine-induced hypothermia and 5-hydroxytryptophan (5-HTP)-induced head-twitch in mice. The levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in prefrontal cortex and hippocampus tissue of both mice and rats. Moreover, the extracellular 5-HT in rat hippocampus was assessed by using microdialysis coupled to HPLC with electrochemical detection., Key Findings: Forty-four components were detected in XCHT. XCHT significantly reduced immobility time in the TST and the FST, antagonized reserpine-induced depressive-like behaviours, increased 5-HTP-induced head-twitches, elevated 5-HT and 5-HIAA levels, and increased 5-HT turnover at doses that did not affect general activity., Conclusions: These data demonstrate that XCHT has therapeutic effects in animal models of depression by enhancing the serotoninergic system in the prefrontal cortex and hippocampus., (© 2013 Royal Pharmaceutical Society.)

Ethnopharmacological relevance Xiaochaihutang (XCHT), a famous Chinese herbal formula which consists of seven Chinese herbs, has been used clinically in depressive disorders in China. Our previous studies have demonstrated that XCHT improved depressive-like behavior in several animal models of depression. However, therapeutic basis of XCHT on depression are challenging, due to the complex active constituents of XCHT and the unclear pharmacological mechanism of action. Materials and methods To provide further insights into therapeutic basis of XCHT, the core in compatibility of XCHT on antidepressant therapy was assessed by the method of orthogonal array design. The comparative evaluations on antidepressant effects of XCHT and its core in compatibility were executed by tail suspension test (TST), forced swim test (FST), novelty suppressed feeding test (NSFT), reserpine-induced hypothermia and palpebral ptosis. Moreover, the potential mechanism was explored by investigating levels of monoamine neurotransmitters in hypothalamus and striatum and neurogenesis in hippocampus. Chemical profile of active constituents in plasma after oral administration of the core in compatibility of XCHT was revealed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). Results The results of orthogonal array design experiment showed that Huangqin (Radix scutellariae), Renshen (Ginseng) and Gancao (Radix glycyrrhizae), defined as HRG, might be the core in compatibility of XCHT on antidepressant therapy. In accordance with XCHT, oral administration of HRG for 15 days significantly reduced immobility duration in TST and FST without affecting locomotor activity. Both HRG and XCHT increased immobility latency in FST, decreased the latency in NSFT, reversed reserpine-induced hypothermia and palpebral ptosis. Moreover, both HRG and XCHT significantly increased levels of 5-HT and DA in hypothalamus. In addition, HRG could remarkably increase Ki-67 and doublecortin (DCX) positive cells in hippocampus. A total 25 active constituents in plasma, including 14 prototype components and 11 metabolites, were identified by UPLC–MS/MS after oral administration of HRG. Conclusion The present results reveal that HRG is supposed to be the core in compatibility of XCHT on antidepressant therapy. In accordance with XCHT, HRG exerts significant antidepressant-like effects, which are likely attributed to regulating serotonergic and dopaminergic systems and increasing hippocampal neurogenesis. The constituents identified in plasma after oral administration of HRG may be the potential active ingredients for the treatment of depression. [ABSTRACT FROM AUTHOR]