title: Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models.
abstract: Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide). Preliminary, in vitro 5-HT3 receptor binding affinity was performed in isolated longitudinal muscle-myenteric plexus from the guinea pig ileum. Consequently, neurobehavioral effects of 4i in acute and chronic rodent models were evaluated. In addition, involvement of serotonergic system in the postulated effects of the compound was analyzed by in vivo assay. in vitro, 4i demonstrated high 5-HT3 receptor antagonistic activity (pA2, 7.6). in vivo acute study, 4i exhibited decreased duration of immobility in forced swim and tail suspension tests, and increased exploratory parameters as number and duration of nose-poking in hole board test and latency and time spent in aversive brightly illuminated light chamber in light-dark model. Moreover, in chronic model of depression, i.e., olfactory bulbectomy with behavioral deficits, 4i reversed depressive anhedonia in sucrose preference test and anxious hyperactive behavior in open field test in rats. Furthermore, synergistic effect of 4i with fluoxetine (a selective serotonin reuptake inhibitor) and inhibitory effect of 1-(m-chlorophenyl)-biguanide (a 5-HT3 receptor agonist) revealed serotonergic modulation by 4i mediated 5-HT3 receptor antagonism, which was further confirmed by potentiation of 5-hydroxytryptophan (a serotonin synthesis precursor) induced head twitch response. These findings suggest the potential antidepressant and anti-anxiety like effects of 4i, which may be related to the modulation of serotonergic system.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India. Electronic address: deepaligupta2010@gmail.com.
authors.forename: Deepali
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India. Electronic address: rmaheshbits@gmail.com.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Radhakrishnan
authors.affiliation: KVSR Siddhartha College of Pharmaceutical Sciences, Vijaywada, Andhra Pradesh 520001, India. Electronic address: tdevadoss@gmail.com.
authors.forename: Devadoss
authors.initials: D
authors.lastname: Thangaraj
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India. Electronic address: yashkurhe@gmail.com.
authors.forename: Yeshwant
authors.initials: Y
authors.lastname: Kurhe
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; C000594644:N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide; D011810:Quinoxalines; D058831:Serotonin 5-HT3 Receptor Antagonists; D012701:Serotonin; C045918:2-methyl-5-HT
keywords: 5-HT(3) receptor antagonist; Anxiety; Depression; Fluoxetine (PubChem CID: 3386); Forced swim test; Hole board test; Olfactory bulbectomy; Serotonin (PubChem CID: 5202)