The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.