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Item Anti-depressant - Like Effect of Novel 5-HT Receptor Antagonist, (4- 3 benzylpiperazin-1-yl) (3-methoxyquinoxalin-2-yl)methanone (6g) in Acute and Chronic Animal Models of Depression(IJPER, 2013-03) Mahesh, R.A novel 5-HT receptor antagonist '6g' with a good log P and pA value identified from a series of compounds synthesized in our laboratory was subjected to forced 3 2 swim test (FST) (1 and 2 mg/kg, i.p) and tail suspension test (TST) (0.5–2 mg/kg, i.p.). Compound 6g significantly reduced the duration of immobility in mice without affecting the base line locomotion. Moreover, 6g (1 and 2 mg/kg, i.p.), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and reversed the reserpine-induced hypothermia (RIH) in rats. In interaction studies of 6g with various standard drugs/ligands using FST, 6g (1 mg/kg, i.p.) potentiated the anti-depressant effect of venlafaxine, desipramine and fluoxetine. Moreover, 6g (1 and 2 mg/kg, i.p.) influenced the effect of 8-OH DPAT and harmane as well as reverse the effect of parthenolide by reducing the duration of immobility in FST. However, 6g (1 and 2 mg/kg, i.p.) has no influence on mCPP induced increase in duration of immobility in FST. Furthermore, 6g (1 mg/kg, i.p.) potentiated the effect of bupropion in TST. Chronic 6g treatment attenuated the behavioral anomalies in olfactory bulbectomy (OBX) rats. In conclusion, these various findings reiterated the anti-depressant-like effects of 6g in behavioral models of depression.Item Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression(IJPER, 2015-02) Mahesh, R.The hope of developing better antidepressants has stimulated research on 5-HT receptor, capable of producing diverse antidepressant-like 7 behavioral effects. In the current study, the pimozide, a novel 5-HT receptor antagonist, was screened for its antidepressant potential in 7 rodent's behavioral test battery. Psycho-pharmacological investigations involved acute and chronic treatment (14 days) of pimozide in forced swim test (FST), tail suspension test (TST) in mice and olfactory bulbectomy in rats, respectively. Dose response study in mice FST and TST revealed the initial antidepressant-like effect of pimozide (0.5-4mg/kg i.p.). Interaction studies revealed that pimozide (1and 2mg/kg) significantly enhanced the antidepressant action of citalopram and bupropion in mice FST and TST respectively. Reversal of reserpine induced hypothermia (rats) was observed at same dose level. Further, the behavior anomalies exhibited by olfactory bulbectomised rats (OBX) were attenuated by chronic pimozide treatment as observed in open field and hyper-emotionality tests. In conclusion, this behavioural study depicts the antidepressant-like effect of pimozide in rodent's behavioural model.Item Antidepressant-like effect of a novel 5-HT3 receptor antagonist N-(benzo[d] thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide 6k using rodents behavioral battery tests(Sage, 2014-09) Mahesh, R.To investigate the antidepressant-like effect of N-(benzo[d] thiazol-2-yl)-3- ethoxyquinoxalin-2-carboxamide 6k, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist using rodents behavioral battery tests.Item Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression(IJPER, 2015-02) Mahesh, R.The hope of developing better antidepressants has stimulated research on 5-HT receptor, capable of producing diverse antidepressant-like 7 behavioral effects. In the current study, the pimozide, a novel 5-HT receptor antagonist, was screened for its antidepressant potential in 7 rodent's behavioral test battery. Psycho-pharmacological investigations involved acute and chronic treatment (14 days) of pimozide in forced swim test (FST), tail suspension test (TST) in mice and olfactory bulbectomy in rats, respectively. Dose response study in mice FST and TST revealed the initial antidepressant-like effect of pimozide (0.5-4mg/kg i.p.). Interaction studies revealed that pimozide (1and 2mg/kg) significantly enhanced the antidepressant action of citalopram and bupropion in mice FST and TST respectively. Reversal of reserpine induced hypothermia (rats) was observed at same dose level. Further, the behavior anomalies exhibited by olfactory bulbectomised rats (OBX) were attenuated by chronic pimozide treatment as observed in open field and hyper-emotionality tests. In conclusion, this behavioural study depicts the antidepressant-like effect of pimozide in rodent's behavioural model.Item Antidepressant-like effect of a novel 5-HT3 receptor antagonist N-(benzo[d] thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide 6k using rodents behavioral battery tests(Sage, 2014-09) Mahesh, R.To investigate the antidepressant‑like effect of N‑(benzo[d] thiazol‑2‑yl)‑3‑ ethoxyquinoxalin‑2‑carboxamide 6k, a 5‑hydroxytryptamine type 3 (5‑HT3) receptor antagonist using rodents behavioral battery tests. Materials and Methods: 6k screening was performed with behavioral assays for depression‑like forced swim test (FST) at several single doses (0.25-4 mg/kg, intraperitoneal injection (i.p.)) to test the potency of 6k, in which 2 and 4 mg/kg doses were found to be most effective and hence, in further behavioral assays including mechanistic model like 5‑hydroxytryptophan (5‑HTP)‑induced head twitches was performed in mice at acute doses of 6k (2 and 4 mg/kg, i.p.). Furthermore, olfactory bulbectomy (OBX), a surgical model‑induced behavioral alterations was performed in rats, and the effect of 6k administered orally (2 and 4 mg/kg, p.o.) after subchronic treatment for 14 days starting from day 15 of postsurgery was examined by percent sucrose preference test and modified open field test (OFT). Results: 6k (1, 2, and 4 mg/kg, i.p.) reduced the immobility time and increased the swimming behavior in FST without affecting the baseline locomotor score showing antidepressant‑like effect. 5‑HTP‑induced head twitch response was potentiated by 6k (2 and 4 mg/kg, i.p.), which indicated rise in the serotonergic neurotransmission in the brain. 6k (2 and 4 mg/kg, p.o.) showed anti‑anhedonia effect by increasing the sucrose consumption and reversed the behavioral alterations when exposed to modified open field in OBX rats after subchronic treatment for 14 days, thus exhibiting antidepressant‑like effect. Conclusion: 6k attenuated the behavioral derangement in rodents‑based behavioral battery tests for depression, indicating antidepressant‑like potential.Item Effects of adhatoda vasica leaf extract in depression co‑morbid with alloxan‑induced diabetes in mice(IJGP, 2014) Mahesh, R.Context: Increased neuronal oxidative stress as a consequence of diabetes may result in neuropsychological complications such as depression. Depression co‑morbid with diabetes further hampers the quality life years in diabetic patients. Aim: Thus, the present study was aimed at investigating the effects of Adhatoda vasica leaf extract (EAV), as a natural remedy, in alloxan‑induced diabetes and co‑morbid depression in mice. Materials and Methods: Experimentally, mice were rendered diabetic with a single dose of alloxan of 200 mg/kg, intraperitoneally (i.p.). After 3 weeks of having chronic diabetic state, mice were given EAV (100-400 mg/kg, orally)/ vehicle/standard control (escitalopram, ESC; 10 mg/kg, orally) for 7 days. After dosing, anti‑diabetic effect was detected by the fasted blood glucose levels and anti‑depressant effect was evaluated by behavioural despair tests, followed by monoamine oxidase (MAO) activity and oxidative stress analysis. Results and Discussion: EAV treatment effectively reduced the elevated blood glucose levels and reversed co‑morbid depressive behaviour. Furthermore, EAV inhibited diabetes induced increased oxidative stress and MAO activity in the brain. Thus, EAV demonstrated the potential protective action against oxidative stress and revealed monoamine modulatory activity in the brain, which may contribute to its anti‑depressant effect. Conclusion: This work demonstrates the efficacious effect of EAV in reversing the depression co‑morbid with alloxan‑induced diabetes in mice.Item Anti-depressant-like activity of a novel serotonin type-3 (5-HT3) receptor antagonist in rodent models of depression(NISCAIR, 2011) Mahesh, R.N-Cyclohexyl-3-methoxyquinoxalin-2-carboxamide (QCM-13), a novel 5-HT3 antagonist identified from a series of compounds with higher pA2 (7.6) and good log P (2.91) value was screened in rodent models of depression such as forced swim test (FST), tail suspension test (TST), interaction studies with standard anti-depressants and confirmatory studies such as reversal of parthenolide induced depression and reserpine induced hypothermia. In FST (2 and 4 mg/kg) and TST (2 and 4 mg/kg), QCM-13 significantly reduced the duration of immobility in mice without affecting the base line locomotion. QCM-13 (2 and 4 mg/kg) was also found to have significant interaction with standard anti-depressants (fluoxetine and bupropion in FST and TST respectively). Further, reversal of parthenolide induced depression in mice and reserpine induced hypothermia in rat models indicate the serotonergic influence of QCM-13 for anti-depressant potential.Item Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT3 receptor antagonist: An investigation in behaviour-based rodent models of depression(Wolters Kluwer, 2012-09) Mahesh, R.The present study was designed to investigate the antidepressant potential of (4-phenylpiperazin-1-yl) (quinoxalin-3-yl) methanone (4a), a novel 5-HT3 receptor antagonist, with an optimal log P (2.84) and pA2 value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression.Item Antidepressant-like effect of novel 5-HT3 receptor antagonist N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p): An approach using rodent behavioral antidepressant tests(Wolters Kluwer, 2013) Mahesh, R.The present study was designed to investigate the antidepressant potential of N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p), a novel 5-HT3 receptor antagonist in rodent behavioral models of depression.Item Antidepressant-like activity of 2-(4-phenylpiperazin-1-yl)-1, 8-naphthyridine-3-carboxylic acid (7a), a 5-HT3 receptor antagonist in behaviour based rodent models: Evidence for the involvement of serotonergic system(Elsevier, 2013-08) Mahesh, R.The present study was designed to investigate the putative antidepressant-like activity of 7a, a 5-HT3 receptor antagonist, (although indirect evidence of 5-HT3 antagonism) with an optimal log P (3.35) and pA2 value (7.6) greater than ondansetron (pA2 — 6.6) using behavioural tests battery of depression. Acute treatment of 7a (0.5-2 mg/kg, i.p.) in mice produced antidepressant-like effects in forced swim test (FST) and tail suspension test (TST) without affecting the baseline locomotion in actophotometer test in mice. Moreover, the combination of a sub-effective dose of 7a (0.25 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) produced an anti-immobility effect in mouse FST. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days) and 1-(m-Chlorophenyl)-biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT3 receptor agonist) prevented the anti-immobility effects of 7a (2 mg/kg, i.p.) in the mouse FST. In addition, 7a (0.5–2 mg/kg, i.p.) treatment also potentiated the 5-hydroxytryptophan (5-HTP) and pargyline induced head twitch response in mice. Furthermore, sub-chronic treatment (14 days) with 7a (0.5–2 mg/kg, i.p.) and paroxetine (10 mg/kg, i.p.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in a modified open field paradigm. These results suggest that the antidepressant-like action of 7a may be mediated by an interaction with the serotonergic system and this molecule should be further investigated as an alternative therapeutic approach for the treatment of depression.