Involvement of nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tropisetron and ondansetron in mice forced swimming test and tail suspension test

• 5-HT3 antagonists showed an antidepressant effect in the mouse FST and TST.
• nNOS inhibitor enhanced the effect of 5-HT3 antagonists in behavioral tests.
• NO precursor and 5-PDE inhibitor attenuated the effect of 5-HT3 antagonists.
• 5-HT3 antagonists and nNOS inhibitor decreased the hippocampal nitrite levels.
• Antidepressant effect of 5-HT3 antagonists is partly mediated via NO-cGMP pathway.

Antidepressant-like effects of 5-hydroxytryptamine subtype 3 (5-HT3) antagonists including tropisetron and ondansetron have been previously demonstrated in the literature. It was reported that stimulation of 5-HT3 receptors activate the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, which is involved in regulation of behavioral and emotional functions. In our study, treating animals with tropisetron (5, 10, and 30 mg/kg) and ondansetron (0.01 and 0.1 µg/kg) significantly decreased the immobility time in forced swimming test (FST) and tail-suspension test (TST). Co-administration of subeffective doses of tropisetron (1 mg/kg) and ondansetron (0.001 µg/kg) with subeffective dose of l-NAME (10 mg/kg, nonselective NO synthase (NOS) inhibitor) and 7-nitroindazole (25 mg/kg, neural NOS inhibitor) exerted antidepressant-like effect in FST and TST, while aminoguanidine (50 mg/kg, inducible NOS inhibitor) did not enhance the antidepressant-like effect of 5-HT3 antagonists. Besides, l-arginine (750 mg/kg, NO precursor) and sildenafil (5 mg/kg, phosphodiesterase inhibitor) suppressed the anti-immobility effect of 5-HT3 antagonists. None of the treatments altered the locomotor behavior of mice in open-field test. Also, hippocampal (but not cortical) nitrite level was significantly lower in tropisetron and ondansetron-treated mice compared with saline-injected mice. Also, co-administration of 7-nitroindazole with tropisetron or ondansetron caused a significant decrease in hippocampal nitrite levels. In conclusion, we suggest that antidepressant-like effect of tropisetron and ondansetron are partially mediated by modulation of NO-cGMP pathway.

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