Objective: To explore the effects of Kaixin Powder (开心散, KXP) on melatonin receptor (MR) expression and 1261-Mel binding affinity in a depression rat model. Methods: Seventy-two male Wistar rats were divided into six groups: a blank control group, model group, ramelteon group, KXP high-dosage group (HKXP), medium-dosage group (MKXP) and low-dosage group (LKXP). To establish the depression model, all groups except the blank control group were singly housed and exposed to chronic unpredictable mild stress. Weight gain, sucrose consumption and the open-field test were used to evaluate induction of depression. KXP at 260, 130 and 65 mg/(kg·d) was also respectively administered to the rats in the HKXP, MKXP and LKXP groups for 21 days. Ramelteon [0.83 mg/(kg·d)] was given to the positive drug control group. An equivalent volume of physiological saline was given to the blank and model groups. The liquid chip method was used to measure the concentration of plasma melatonin (MT). Mell a (MT1) and Mellb (MT2) expression levels were determined by Western blotting. In addition, a radioactive ligand-binding assay was used to analyze the specific binding properties and dynamic characteristics between MR and 125I-Mel. Results: The results of weight gain, sucrose consumption and the open-field test showed that our model successfully produced depressive symptoms and depressive-like behavior. The concentration of plasma MT in the model group decreased significantly at night but increased in the MKXP group (P〈0.05). The HKXP group showed significantly increased expression of MT1 (P〈0.05); however, the expression of MT2 in all groups exhibited no significant differences (P〉0.05). The maximum binding capacity (Bmax) for specific binding between MR and 125I-Mel in the MKXP group was significantly higher than that in the model group (P〈0.05), but no significant differences were found in the equilibrium dissociation constant (Kd) of each group (P�