This study investigated the possible antidepressant-like and anxiolytic-like effects of diphenyl diselenide, (PhSe)(2) in mice. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the antidepressant-like effect was also evaluated. The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced by (PhSe)(2) (5-100 mg/kg; oral route, p.o.). The antiimmobility effect of (PhSe)(2) (5 mg/kg, p.o.) in the TST was prevented by pretreatment of mice with L-arginine [a substrate for nitric oxide synthase (NOS)], methylene blue [an inhibitor of NO synthase and sGC] and sildenafil [a phosphodiesterase 5 inhibitor]. Furthermore, a sub-effective dose of (PhSe)(2) (0.1 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine [L-NNA; 0.3mg/kg, i.p. inhibitor of NOS], (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ; 30 pmol/site i.c.v., a specific inhibitor of soluble guanylate cyclase (sGC)], fluoxetine and imipramine in the TST. (PhSe)(2) (50-100 mg/kg, p.o.) induced anxiolytic-like effect in the elevated plus-maze test and light/dark box. Together the results indicate that (PhSe)(2) elicited significant antidepressant-like and anxiolytic-like effects. The antidepressant-like action caused by (PhSe)(2) seems to involve an interaction with L-arginine-NO-cGMP pathway.