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In this study, we evaluated the involvement of N-methyl- d-aspartate receptor (NMDAR)/nitric oxide (NO) system on the antidepressant-like effects of paroxetine in the mouse forced swimming test. Swim sessions were conducted by placing mice in individual glass cylinders filled with water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. Paroxetine (8 and 16 mg/kg, intraperitoneal [i.p.]) significantly reduced the immobility times of mice, whereas lower doses (2 and 4 mg/kg) had no effect. NMDA antagonists MK-801 (0.1 and 0.25 mg/kg, i.p.) and ifenprodil (1 and 3 mg/kg, i.p.) and the NO synthase inhibitor NG- l-arginine methyl ester (L-NAME; 30 and 100 mg/kg, i.p.) significantly decreased the immobility time. Lower doses of MK-801 (0.01 and 0.05 mg/kg), ifenprodil (0.1 and 0.5 mg/kg), and L-NAME (10 mg/kg) had no effect. Combined treatment of subeffective doses of paroxetine (4 mg/kg) and MK-801 (0.05 mg/kg), ifenprodil (0.5 mg/kg), and L-NAME (10 mg/kg) robustly exerted an antidepressant-like effect. The noneffective dose of a NO precursor l-arginine (750 mg/kg, i.p.) prevented the antidepressant-like effect of paroxetine (30 mg/kg). We suggested, for the first time, a possible role for NMDAR/NO signaling in the antidepressant-like effects of paroxetine, providing a new approach for the treatment of depression. [ABSTRACT FROM AUTHOR]