Effect of a novel 5-HT₃ receptor antagonist carboxamide, 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on the acute and chronic rodent models of depression

Objective: 5-HT₃ receptor the only type of ion channel among the family of serotonergic receptors which is recognized as a potential novel therapeutic target for depression, anxiety and cognition. In the present work was designed to evaluate the antidepressant-like effect of a novel 5-HT₃ antagonist carboxamide, 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in a battery of behavioral acute and chronic rodent models of depression. Methods: Behavioral models with high predictive validities like forced swim test (FST) and tail suspension test (TST) in mice along with mechanistic models including 5-hydroxytryptamine (5-HTP) induced head twich response in mice and reserpine induced hypothermia in rats were used for screening QCM-4. Chronic surgical model of olfactory balbectomy (OBX) was performed and further evaluated by sucrose preference test and open field test (OFT) for anti-depressant like effect of QCM-4. Results: Following were the principle findings in the present research; Firstly, QCM-4 dose dependently reduced the immobility duration in FST and TST. Secondly, in the mechanistic models, QCM-4 dose dependently potentiated 5-HTP induced head twich response and attenuated the reserpine induced hypothermia. Lastely, in the surgical OBX model, QCM-4 reversed the anhedonia and behavioral alterations in animals which was evaluated by increase in the sucrose consumption and reduction in ambulation, fecal contents as well as number of rearings in OFT by QCM-4 treated OBX animals compared to OBX control. Conclusion: The results of the present study, indicates that QCM-4, a novel 5-HT₃ receptor antagonist exhibit an anti-depressant like effect. Our further studied will be focused on the chronic unpredictable mild stress induced alterations and molecular mechanism involved in the anti-depressant like action of QCM-4.