title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-BITS, Pilani, Rajasthan 333031, India. dev.nuru@gmail.com
authors.forename: Baldev Kumar
authors.initials: BK
authors.lastname: Gautam
authors.forename: Ankur
authors.initials: A
authors.lastname: Jindal
authors.forename: Arghya Kusum
authors.initials: AK
authors.lastname: Dhar
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Mahesh
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology*; D009830:Olfactory Bulb / Q000601:surgery; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*
chemical_list: C585446:2-(4-phenylpiperazin-1-yl)-1,8-naphthyridine-3-carboxylic acid; D018687:Antidepressive Agents, Second-Generation; D009287:Naphthyridines; D010879:Piperazines; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists