Abstract: This study is to explore the possible mechanisms of the antidepressant-like effect of agmatine. By using two traditional “behavior despair” model, tail suspension test and forced swimming test, we examined the effects of some monoamine receptor antagonists (including β-adrenergic receptor antagonist propranolol, β-adrenergic receptor antagonist/5-HT_1A/1B receptor antagonist pindolol, α₂-adrenergic receptor antagonists yohimbine and idazoxan and 5-HT₃ receptor antagonist tropisetron) on the antidepressant-like action of agmatine in mice. Activity of adenylate cyclase (AC) in the synapse membrane from rat frontal cortex was determined by radioimmunoassay. Single dose of agmatine (5-40 mg·kg^-1，ig) dose-dependently decrease the immobility time in tail suspension test in mice, indicating an antidepressant-like effect. The effect of agmatine (40 mg·kg^-1, ig) was antagonized by co-administration of β-adrenergic receptor antagonist/5-HT_1A/1B receptor antagonist pindolol (20 mg·kg^-1, ip), α₂-adrenergic receptor antagonists yohimbine (5-10 mg·kg^-1, ip) or idazoxan (4 mg·kg^-1, ip), but not β-adrenergic receptor antagonist propranolol (5-20 mg·kg^-1, ip) and 5-HT₃ receptor antagonist tropisetron (5-40 mg·kg^-1, ip). Agmatine (5-40 mg·kg^-1, ig) also dose-dependently decrease the immobility time in forced swimming test in mice. The effect of agmatine (40 mg·kg^-1, ig) was also antagonized by pindolol (20 mg·kg^-1, ip), yohimbine (5-10 mg·kg^-1, ip), or idazoxan (4 mg·kg^-1, ip). Incubation of agmatine (0.1-6.4 μmol·L^-1) with the synaptic membrane extracted from rat frontal cortex activated the AC in a dose-dependent manner in vitro. While the effect of agmatine (6.4 μmol·L^-1) was dose-dependently antagonized by pindolol (1 μmol·L^-1) or yohimbine (0.25-1 μmol·L^-1). Chronic treatment with agmatine (10 mg·kg^-1, ig, bid, 2 w) or fluoxetine (10 mg·kg^-1, ig, bid, 2 w)increased the basic activity, as well as the Gpp(NH)p (1-100 μmol·L^-1) stimulated AC activity in rat prefrontal cortex. These results indicate that regulation on 5-HT_1A/1B and α₂ receptors, and activation AC in the frontal cortex is one of the important mechanisms involving in agmatine’s antidepressant-like action.