This study investigated the involvement of 5-HT(1) and 5-HT(2) receptors in the antidepressant-like effect of agmatine in the mouse forced swimming test (FST). Pretreatment with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, intraperitoneally (i.p.), an inhibitor of serotonin synthesis, for 4 consecutive days), methysergide (5 mg/kg, i.p., a serotonin (5-HT) antagonist), pindolol (32 mg/kg, i.p., a 5-HT(1A/1B) receptor/beta-adrenoceptor antagonist), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635; 0.3 mg/kg, subcutaneously (s.c.), a selective 5-HT(1A) receptor antagonist), 1-(2-methoxyphenyl)-4[-(2-phthalimido)butyl]piperazine) (NAN-190; 0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane; 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT(2) antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), prevented the effect of agmatine (10 mg/kg, i.p.) in the FST. A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with pindolol (32 mg/kg), NAN-190 (0.5 mg/kg, i.p.), WAY 100635 (0.03 mg/kg, s.c.), (+)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT; 0.01 mg/kg, i.p., a 5-HT(1A) receptor agonist), R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI; 1 mg/kg, i.p., a preferential 5-HT(2A) receptor agonist), or fluoxetine (10 mg/kg, i.p., a selective serotonin reuptake inhibitor, SSRI) but not with isamoltane (2.5 mg/kg, i.p.), ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or ketanserin (5 mg/kg, i.p.). Taken together, the results firstly demonstrate that agmatine antidepressant-like effects in the FST seem to be mediated, at least in part, by an interaction with 5-HT(1A/1B) and 5-HT(2) receptors.