Effect of acute and chronic treatment with QCF-3 (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone, a novel 5-HT3 receptor antagonist, in animal models of depression

Abstract

The serotonin type 3 (5-HT(3)) receptor is unique among the seven recognized serotonin receptor "families". The existence serotonin type 3 receptor (5-HT(3)) in neuro-anatomical regions stimulated the research interest for novel therapeutic targets such as anxiety, depression, nociception and cognitive function. In the current study, (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone (QCF-3), a novel 5-HT(3) receptor antagonist, with an optimal log P (the logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P) and significant pA2 value (is a negative logarithm of the molar concentration of antagonist required to reduce the effect of multiple dose agonist to that of single dose) was screened for its anti-depressant potential using rodent behavioral models of depression. Psycho-pharmacological investigations involved acute and chronic treatment (14 days) with QCF-3 and assessment of behavior during the forced swim test (FST) and tail suspension test (TST) in mice and olfactory bulbectomised rats. A dose response study in mice revealed an initial anti-depressant-like effect of QCF-3 (0.5-4 mg/kg, ip) in the FST and TST. Interaction studies showed that QCF-3 (1 and 2 mg/kg) significantly enhanced the antidepressant action of fluoxetine and bupropion in the FST and TST, respectively. QCF-3 (1 and 2 mg/kg) potentiated the 5-hydroxytryptophan (5-HTP) induced head twitches response in mice and reversed reserpine-induced hypothermia in rats. Further, OBX rats exhibited behavioral anomalies in the open field and hyper-emotionality tests that were attenuated by chronic QCF-3 treatment. In conclusion, this behavioral study describes an antidepressant-like effect of QCF-3 in rodent behavioral models of depression.

Contribution of serotonin type 3 receptors in the successful extinction of cued or contextual fear conditioned responses: interactions with GABAergic signaling

“…These results provide additional support that repeated treatment with granisetron on days 1 and 4 produced lower states of anxiety as reflected by a significantly lower percentage of freezing in these animals when compared with the saline controls. Similar to the current findings, 14 days of chronic intraperitoneal injections of the 5-HT 3 receptor antagonist ondansetron or (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone reduced rodents' immobility and increased swimming episodes in the forced swim task indicating antidepressant effects of the repeated treatments with ondansetron (Ramamoorthy et al, 2008;Devadoss et al, 2010). In addition, repeated administration of the 5-HT 3 receptor antagonist DAU 6215 for 14 days reduced latencies to find an escape platform and swimming distances to find the platform in a Morris water maze task (Pitsikas et al, 1993).…”

Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice

“…Earlier reports have evidenced the antidepressant and anxiolytic-like effects of novel 5-HT 3 receptor antagonists (like MCI-225) in rodent behavioral models [28,29]. Also the recent findings have revealed that novel compounds with potential 5-HT 3 antagonistic activity exhibit antidepressant and anxiolytic-like effects [30,31]. In addition, the findings that the different classes of antidepressants are functional antagonists at 5-HT 3 receptors convincingly support the potential activity of 5-HT 3 antagonists in attenuating depression-like behavior [32].…”

Antidepressant activity of Simvastatin in behavioral models of depression in rats

“…These FST models were chosen as they are widely used to screen antidepressant drugs. 12 In FST rats are forced to swim in a restricted space from which they cannot escape. The rats are induced to a characteristic behavior of immobility and this behavior reflects a state of despair that can be reduced by several agents which are therapeutically effective in human depression.…”