title: Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India.
authors.forename: Deepali
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Radhakrishnan
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India.
authors.forename: Yeshwant
authors.initials: Y
authors.lastname: Kurhe
authors.affiliation: KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh-520001, India.
authors.forename: Devadoss
authors.initials: D
authors.lastname: Thangaraj
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India.
authors.forename: Visakh
authors.initials: V
authors.lastname: Prabhakar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan-333031, India.
authors.forename: Prateek
authors.initials: P
authors.lastname: Kanade
mesh_terms: D000208:Acute Disease; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D006168:Guinea Pigs; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011810:Quinoxalines / Q000494:pharmacology*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects* / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D000975:Antioxidants; D052160:Benzothiazoles; D015415:Biomarkers; C000600489:N-(benzo(d)thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D005473:Fluoxetine; D003345:Corticosterone