Abstract: ob＜x＞jective: The purpose of our study was to investigate the role of exogenous dynorphin in activating the к receptors in ventral tegmental area(VTA) in the regulation of depression-related despairing behavior of mice. Methods: The tailored cannula was implanted into the VTA through Stereotaxic technology and verified morphologically. The tail suspension test (TST) and forced swimming test (FST) were used to measure the degree of desperation associated with depression in mice. Results: We found that intra-VTA administration of exogenous dynorphin activating its к receptors increased the immovable time of mice in the TST and FST, and this effect can be completely blocked by pretreatment of microinjecting of nor-Binaltorphimine (nor-BNI), a specific к receptor antagonist. Conclusions: These findings reveal that dynorphin activating VTA к receptors could induce depression related despairing behaviors, which was reversed by pretreatment of microinjecting exogenous nor-BNI, the specific antagonist of к receptor.