The effects of inhibitors of different subtypes of potassium (K+) channels were investigated in the mouse forced swimming test (FST). The treatment of animals with tetraethylammonium (TEA, a non-specific inhibitor of potassium channels, 0.25-2.5 ng/site, intracerebroventricular, i.c.v.), glibenclamide (an ATP-sensitive potassium channels (K(ATP) inhibitor, 0.05-5 ng/site, i.c.v.), apamine (a small conductance calcium-activated potassium channels inhibitor (SKCa), 0.1-1 ng/site, i.c.v.), charybdotoxin (a large- (big, BK) and intermediate- (IK) conductance calcium-activated potassium channels inhibitor, 2.5-25 ng/site, i.c.v.) produced an anti-depressant-like effect in the FST. At the highest effective doses, none of the drugs affected the locomotor activity in an open-field. Besides that, the pre-treatment of animals with l-arginine (a nitric oxide (NO) precursor, 750 mg/kg, intraperitoneal, i.p.) or sildenafil (a specific phosphodiesterase type 5 (PDE5) inhibitor, 5 mg/kg, i.p.) prevented the anti-depressant-like effect of all K+ channel inhibitors. The present results demonstrate that the decrease in the immobility time in the FST elicited by the inhibition of several subtypes of K+ channels is also dependent on the inhibition of NO-cGMP synthesis.