Recent findings have indicated that nitric oxide (NO) may change the duration of immobility biphasically in the forced swimming test, which is a useful experimental model for screening antidepressant-like activity in rodents. In the present study, we have investigated the role of serotonin and of potassium (K) channels in the dual effects of NO in the mouse forced swimming test (MFST). For this purpose, we tested the effects Of L-arginine, an NO precursor, the NO synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME), and of K+ -channel blockers tetraethylammonium (TEA) and 3,4-diaminopyridine (3,4-DAP). In addition, we used sertraline as a serotonin reuptake inhibitor and cyproheptadine as a serotonin antagonist. L-Arginine increased the duration of immobility in the MFST in low doses (25 mg/kg ip) but decreased it in higher doses (500 and 1000 mg/kg ip). Low doses Of L-NAME (50 and 75 mug icv) decreased while higher dose of this drug (150 mug icv) increased the immobility time. TEA (5 mug icv) and 3,4-DAP (0.05 mug icv) significantly reduced the time, whereas K+ channel opener pinacidil increased the duration of immobility. L-Arginine (100 mg/kg ip) significantly antagonised the effects Of L-NAME (50 mug), 3,4-DAP and TEA. Higher dose Of L-arginine (500 mg/kg ip) significantly potentiated the effects of 3,4-DAP and TEA, but reduced the effect of pinacidil. Low doses Of L-arginine antagonized, but higher doses Of L-arginine potentiated the antidepressant-like effect of sertraline. Sertraline potentiated the effects of 3,4-DAP and TEA, but reversed the effect of pinacidil. Cyproheptadine reduced the anti-immobility effect Of L-arginine and 3,4-DAP. At the highest effective doses, drugs did not impair the motor functions. These data support the hypothesis that NO effects may involve the release of serotonin and/or modulation of K+ channels. (C) 2004 Elsevier Inc. All rights reserved.