Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice

• Published in: PloS one 2017-11, Vol.12 (11), p.e0187445-e0187445
• Main Authors: Fronza, Mariana G, Brod, Lucimar M Pinto, Casaril, Angela Maria, Sacramento, Manoela, Alves, Diego, Savegnago, Lucielli
• Format: Article
• Language: English
• Subjects: Affinity; Animals; Antidepressants; Antidepressive Agents - therapeutic use; Antifungal agents; Antioxidants; Biological computing; Biological effects; Biology and Life Sciences; Care and treatment; Computer applications; Conformation; Depression (Mood disorder); Diagnosis; Docking; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine transporter; Dosage and administration; Dose-Response Relationship, Drug; Drug dosages; Fluoxetine; Ketanserin; Kinases; Locomotor activity; Male; Medicine and Health Sciences; Mental depression; Mice; Models, Molecular; Open-field behavior; Organoselenium Compounds - pharmacology; Oxidative stress; Physical Sciences; Pretreatment; Receptors; Selenium; Serotonin; Serotonin - physiology; Serotonin Antagonists - therapeutic use; Serotonin Receptor Agonists - therapeutic use; Serotonin receptors; Serotonin transporter; Sulpiride; Swimming; Transporter; Triazoles - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187445

A series of phenylselanyl-1H-1,2,3-triazole-4-carbonitriles with different substituents were screened for their binding affinity with serotonin transporter (SERT) and dopamine transporter (DAT) by docking molecular. 5-(4methoxyphenyl)-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (SeTACN) exhibited the best conformation with SERT even higher than fluoxetine and serotonin, suggesting a competitive inhibition. SeTACN demonstrated additional affinity to other serotonergic receptors involved in antidepressant effects: 5HT1a, 5HT2a and 5HT3. In another set of experiments, SeTACN led to significant reductions in the immobility time of mice submitted to forced swimming test (FST) in the dose range of 0.1- 20mg/kg, suggesting an antidepressant-like effect. The possible mechanism of action was investigated using serotonergic and dopaminergic antagonists. The antidepressant-like effect of SeTACN (0.1mg/kg i.g.) was prevented by the pretreatment with WAY100635 (a selective 5HT1a antagonist), ketanserin (a 5HT2a/c antagonist) and ondansetron (a selective 5ht3 antagonist), PCPA (an inhibitor of serotonin synthesis) but not with SCH23390 (dopaminergic D1 antagonist) and sulpiride (D2 antagonist). Sub-effective dose of fluoxetine was able to potentiate the effects of a sub-effective dose of SeTACN in FST. None of the treatments affected locomotor activity in open field test (OFT). These results together, suggest that the SeTACN antidepressant-like effect is mediate, at least in parts, by serotonergic system.