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, 200 mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1 mg/kg/day, i.p.), fluoxetine (10 mg/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 (1 mg/kg/day, i.p.) after 1 h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10 mg/kg/day, i.p.) treatment and subjected to the same protocol.