Monoaminergic and L-Arginine-NO-cGMP Pathways Mediate the Antidepressant–like Action of Alkaloids from the Stem Bark of Trichilia monadelpha

Abstract Background: The role of L-arginine-nitric oxide-cGMP and monoamine pathways in the pathophysiology of depression and as target for antidepressant drugs is well documented. Previously, we reported that Trichilia monadelpha possesses antidepressant activity. In that study, total alkaloids (ALK) from T. monadelpha showed greatest activity when compared with other phytochemicals. The mechanism of action for ALK in this previous study was, however, not elucidated. Objective: The current study investigated the involvement of the monoaminergic and L-arginine-NO-cGMP pathways in the antidepressant action of ALK. Materials and methods: The modified forced swim test (FST) and tail suspension test (TST) in mice were used as models to investigate the involvement of the monoaminergic and L-arginine-NO-cGMP pathways in the antidepressant action of ALK. ALK doses of 30-300 mg/kg, p.o. were administered to mice. Experimental process involved pre-treating mice with para-chlorophenylalanine [pCPA] (200 mg/kg, i.p.); cyproheptadine (80 mg/kg, i.p.); reserpine (1 mg/kg, s.c.); methyldopa (200 mg/kg, i.p.); and reserpine (1 mg/kg, s.c.) concomitantly administered with methyldopa (200 mg/kg, i.p.), prazosin (3 mg/kg, p.o.) and yohimbine (3 mg/kg, p.o.). NO pathway was assessed by pre-treating mice with L-arginine (750 mg/kg, i.p.), NG-nitro-L-arginine methyl ester [L-NAME] (30 mg/kg, i.p.), methylene blue (10 mg/kg, i.p.) and sildenafil (5 mg/kg, i.p.). Results: The antidepressant-like action of ALK was reversed by pCPA, methyldopa and/or reserpine. Similarly, cyproheptadine was found to decrease the antidepressant-like action of ALK, while a synergistic effect was observed with yohimbine, but not prazosin. The antidepressant-like action of ALK was also decreased by L-arginine and sildenafil. In contrast, a synergistic effect was observed with pre-treatment of L-NAME and methylene blue. Conclusion: The monoaminergic systems and L-arginine-NO-cGMP pathways were found to mediate the antidepressant-like action of ALK.