Abstract: Background: Semen Zizyphi Sponosae (SZS), a traditional Chinese medicine for the treatment of insomnia and anxiety symptoms. The present study aimed to discuss whether total alkaloids from SZS have anti-depression effect and investigate the antidepressant potential of total alkaloids isolated from Semen Zizyphi Sponosae (TAS) and its possible monoaminergic mechanism in mice. Methods: Mouse models of depression including the forced swimming test (FST), the Tail Suspension Test (TST) and Chronic Unpredicted Mild Stress (CUMS) were used to evaluate the effects of TAS. The possible mechanisms were examined by using fluorospectrophotometry to measure monoamine neurotransmitters in mice hippocampus and frontal cortex. The contents of monoamine neurotransmitters including 5-hydroxytryptamine (5-HT), Norepinephrine (NE) and Dopamine (DA). Results: The results showed that intragastric administration of the TAS (5, 10, 20 mg kg-1) or Venlafaxine 9.4 mg kg-1 significantly reduced the duration of immobility in TST and FST. However, the effect was not dose-dependent. TAS 10 and 20 mg kg-1 significantly increases the 5-HT levels in both of the two brain regions. Conclusion: These findings demonstrated that TAS produced an antidepressant-like effect and the mechanism of action involves the serotonergic, noradrenergic and monoamine oxidase enzyme systems although underlying mechanism still remains to be further elucidated.