Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Aim： To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-（benzo[d]thiazol-2-yl）-3-methoxyquinoxalin-2- carboxamide （6z） in acute and chronic murine models of depression. Methods： 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test （TST） was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z （0.5-2 mg/kg, ip）. In chronic depression model mice were exposed to a 4-week chronic unpredictable stress （CUS） protocol, and treated with 6z （0.5-2mg·k-1·d-1, pc） or a positive drug fluoxetine （10 mg·k-1·d-1, pc） in the last 2 weeks, followed by behavioral and biochemical assessments. Results： The 5-HT3 receptor antagonism of 6z （PA2=7.4） in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron （pA2=6.9）. In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group. Conclusion： 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.