The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs.