The role of nitric oxide�cGMP pathway in selegiline antidepressant-like effect in the mice forced swim test

Abstract

Background: Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. Methods: After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. All drugs were given intraperitoneally (ip). Results: Selegiline (10 mg/kg) decreased the immobility time in the FST similar to fluoxetine (20 mg/kg). Pretreatment with L-arginine (NO precursor, 750 mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5 mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1 mg/kg) showed a synergistic antidepressant effect with NG-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10 mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30 mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50 mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10 mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. Conclusions: It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of L-arginine-NO-cyclic guanosine monophosphate pathway. © 2018 Institute of Pharmacology, Polish Academy of Science