The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY) in the mouse forced swimming test, an animal model widely used for the screening of potential antidepressant drugs. In addition, experiments were performed, using agonists and selective antagonists, to assess the potential role of NPY Y(1) and Y(2) receptor subtypes in this model. Complementary studies were performed in an open field apparatus to rule out any changes in locomotor activity that might have interfered with the interpretation of data from the mouse forced swimming test. Intracerebroventricular injections (0.03 nmole-3 nmole) of NPY, [Leu(31)Pro(34)]PYY (Y(1) agonist), NPY(13-36) (Y(2) agonist), BIBP3226, BIBO3304 (Y(1) antagonists) and BIIE0246 (Y(2) antagonist) were performed 30 min prior to testing in the mouse forced swimming test and open field. NPY administration significantly reduced immobility time in a dose dependent manner (p <.01 vs. control group), as did [Leu(31)Pro(34)]PYY (p <.01 vs. control group) and BIIE0246 (p <.05 vs. control group). In contrast, BIBO3304, BIBP3226 and NPY(13-36) did not display any activity at the doses tested. However, pretreatment with BIBO3304 or BIBP3226 significantly blocked the anti-immobility effects of NPY. Data from the open field demonstrated that BIIE0246 increased horizontal ambulation at the dose found to be active in the forced swimming test. Taken together, our results demonstrate that NPY displays antidepressant-like activity in the mouse forced swimming test, and suggest that this activity is mediated by the NPY Y(1) receptor subtype.