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Byline: Visakh. Prabhakar, Deepali. Gupta, Prateek. Kanade, Mahesh. Radhakrishnan Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of [...]

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 (0.5-2 mg·kg−1·d−1, po) or a positive drug fluoxetine (10 mg·kg−1·d−1, po) 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. [ABSTRACT FROM AUTHOR]

Depression is among the common psychiatric disorders, therefore the common pathways and pathogenesis associated with depression is required to be studied. In few years, role of 5-hydroxytryptamine-1A/B (5-HT1A/B) receptors in depressive disorders have been revealed. Both preclinical and clinical studies reported that the potential agonist and antagonist at 5-HT1A/B receptors have significant modulatory effects in depression. However, the collective details regarding the involvement of 5-HT1A/B receptors and the molecular pathways associated in depression is lacking. Thus, the present review evidence the link between 5-HT1A/B receptors in the brain and depression, the possible pathways involved and their alterations in depression. Further, it reviews the preclinical evidences of 5-HT1A/B receptor modulators as antidepressant agents and their effectiveness. The current review also details the clinical relevance of 5-HT1A/B receptors etiopathogenesis of major depression in humans. [ABSTRACT FROM AUTHOR]