Co-administration of a nitric oxide synthase inhibitor and melatonin exerts an additive antidepressant-like effect in the mouse forced swim test

The aim was to assess the combination therapy of nitric oxide synthase inhibitors and melatonin, since they had been separately shown to be as efficacious as conventional antidepressant drugs in pre-clinical antidepressant screening procedures. The Porsolt swim test was conducted to resemble the symptornatolog of major depressive disorder and an open-filed locomotor activity was also used. N(G)-nitro-L-arginine (L-NNA) at 3 mg/kg slightly, but not significantly, reduced the duration of immobility, and increasing the dose to 10 mg/kg was sufficient to attain a significant reduction. On the other hand, the maximal dose of L-NNA (30 mg/kg) was without effect, although a non-significant small increase was observed. The results obtained with L-NNA were in accorldance with a U-shape effect. While 3 mg/kg melatonin was ineffective, a statistically significant decrease in the duration of immobility was determined at the dose of 10 mg/kg. While the combination of ineffective doses (3 mg/kg, each) of L-NNA and melatonin revealed no further inhibition in the duration of immobility, the most effective doses (10 mg/kg, each) caused a more pronounced reduction when compared with those of each drug alone. None of the drugs used in the present study had any effects on locomotor activity over the dose range applied. The combination therapy with L-NNA and melatonin seems to have an additive effect and may be considered as a feasible candidate in attenuating the symptoms of major depressive disorder.