The involvement of the beta3-adrenoceptor in the antidepressant-like effects of the beta3-adrenoceptor-agonist amibegron is addressed in the chronic mild stress, using adrenergic beta3-receptor knockout (Adrb3tm1Lowl) mice. Amibegron (3 mg/kg/day, i.p., 33 days), attenuated the physical alteration due to the application of repeated stress in wild-type littermates, but not in knockout mice. This result suggests that the beta3-adrenoceptor plays a predominant role in mediating antidepressant-like actions of amibegron.