Objective: To determine the mechanisms underlying the anti-depressant effects of Kaixin JieyuDecoction (开心解郁汤, KJD) by investigating the effects of KJD on behavior, monoamine neurotransmitterlevels, and serotonin (5-HT) receptor subtype expression in the brain in a rat model of depression. Methods:The rat depression model was established using chronic unpredictable mild stress (CUMS). Forty-eight SpragueDawley rats were randomly divided into control, depression model (CUMS), CUMS+KJD (7.7 g/kgl-d1 ofcrude drug), and CUMS+fluoxetine (2.4 mg/kgl.d1) groups (n=12 in each group), and the treatments lastedfor 21 days. We regularly evaluated body weight, sucrose consumption, and horizontal and vertical activityscores in open-field tests. The content of the monoamine neurotransmitters 5-HT, norepinephrine (NE), anddopamine (DA) and the DA metabolite homovanillic acid in the cerebral cortex, and 5-HT1A and 5-HT2A receptormRNA in the cerebral cortex and the hippocampus, were determined respectively by high-performance liquidchromatography-coularray electrochemical detector and real-time polymerase chain reaction. Results: Comparedwith the control group, CUMS rats showed a variety of depression-like behavioral changes, including a significantreduction in body weight, sucrose consumption, and horizontal and vertical activity scores in open-field tests(P〈0.05 or ,P〈0.01), and a significant decrease in 5-HT and NE levels and 5-HT2A receptor mRNA expression.In contrast, they showed a significant increase in 5-HT1A receptor mRNA expression in the cerebral cortex. Inthe hippocampus, 5-HT1A receptor mRNA expression was lower whereas 5-HT2A receptor mRNA expressionwas higher than in the control group (P〈0.05 or P〈0.01). Treatment with KJD or fluoxetine partially attenuatedthese changes (,P〈0.05 or ,P〈0.01). Conclusion: KJD could normalize the levels of 5-HT and NE and adjust thebalance of 5-HT2A and 5-HT2A receptor expression in rat cerebrum, and thi