Abstract: OBJECTIVE To investigate the effect of Zuogui Jiangtang Jieyu formulation on sigma-1 receptor/protein kinase C(sigma-1R/PKC) signaling pathway in hypothalamus of diabetic rats with depression. METHODS Animal models of diabetes complicated with depression were established and randomly divided into 4 groups:model group, positive drug group, high and low dose of Zuogui Jiangtang Jieyu formulation group(20.53, 10.26 g·kg^-1). Additionally, the normal rats were belongs to the normal group. After 28 d of intragastric administration, blood glucose in each group was detected. Then the open field test was used to test the autonomic activity of rats. The pathological damage of hypothalamus was detected by HE staining in each group, and the content of corticotropin releasing factor(CRF) in hypothalamus homogenate of rats was detected by ELISA. At last, expression levels of sigma-1R, phosphorylation of PKC and glucocorticoid receptor(GR) in hypothalamus were evaluated by Western-blot. RESULTS Compared with the normal group, the blood glucose level was significantly increased and the activities were significantly decreased in model group(P<0.01). The level of CRF in hypothalamus was significantly increased(P<0.05), while the expression of sigma-1R, p-PKC/PKC, and p-GR/GR were significantly decreased(P<0.05 or P<0.01). Compared with the model group, high dose of Zuogui Jiangtang Jieyu formulation administration rescued the reduction in blood glucose(P<0.05) and improved activities(P<0.01), which in turn reduced the level of CRF in hypothalamus(P<0.05). Furthermore, the high dose of this formulation treatment also increased the expression of sigma-1R, p-PKC/PKC, and p-GR/GR(P<0.05 or P<0.01). CONCLUSION High dose of Zuogui Jiangtang Jieyu formulation can effectively regulate the expression level of sigma-1R, and reduce the content of CRF in hypothalamus by activating sigma-1R/PKC signaling pathway. The above mechanism of this formulation may be related to the effect of hypoglycemic and antidepressant.