title: A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.
abstract: Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India. Electronic address: deepaligupta2010@gmail.com.
authors.forename: Deepali
authors.initials: D
authors.lastname: Gupta
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 and Science, Pilani, Rajasthan 333031, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Radhakrishnan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001645:Biguanides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003866:Depressive Disorder / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D001645:Biguanides; C000594644:N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D005473:Fluoxetine; D012701:Serotonin; C065734:1-(3-chlorophenyl)biguanide
keywords: 5HT(3) receptor antagonist; Depressive phenotypes; Diabetes; Forced swim test; Open field test; Serotonin