Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression
Abstract
Deepali GUPTA1, *, Mahesh RADHAKRISHNAN1, Yeshwant KURHE1, Devadoss THANGARAJ2, Visakh PRABHAKAR1, Prateek KANADE1
1Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India; 2KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh-520001, India
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.
Keywords: depression; antidepressant; 5-HT3 receptor antagonist; carboxamide; fluoxetine; tail suspension test; chronic unpredictable stress; forced swim test; sucrose preference test; oxidative stress; hypothalamic-pituitary-adrenal axis
* To whom correspondence should be addressed.
E-mail deepaligupta2010@gmail.com
Received 2014-05-03 Accepted 2014-07-28
Keywords:
1Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India; 2KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh-520001, India
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.
Keywords: depression; antidepressant; 5-HT3 receptor antagonist; carboxamide; fluoxetine; tail suspension test; chronic unpredictable stress; forced swim test; sucrose preference test; oxidative stress; hypothalamic-pituitary-adrenal axis
* To whom correspondence should be addressed.
E-mail deepaligupta2010@gmail.com
Received 2014-05-03 Accepted 2014-07-28