Previous studies have shown that infusion of brain-derived neurotrophic factor (BDNF) into the midbrain, near the PAG and dorsal/median raphe nuclei, produced analgesia and increased activity in monoaminergic systems. Alterations in monoaminergic activity have also been implicated in the pathogenesis and treatment of depression. The present studies examined the ability of centrally administered BDNF to produce antidepressant-like activity in two animal models of depression, learned helplessness following exposure to inescapable shock and the forced swim test. In the learned helplessness paradigm, vehicle-infused rats pre-exposed to inescapable shock (veh/shock) showed severe impairments in escape behavior during subsequent conditioned avoidance trials, including a 47% decrease in the number of escapes and a 5 fold increase in escape latency, as compared to vehicle-infused rats which received no pre-shock treatment (veh/no shock). Midbrain BDNF infusion (12-24 micrograms/day) reversed these deficits, and in fact, BDNF-infused rats pre-exposed to inescapable shock (BDNF/shock) showed escape latencies similar to veh/no shock and BDNF/no shock rats. In the forced swim test, BDNF infusion decreased the immobility time by 70% as compared to vehicle-infused controls. Non-specific increases in activity could not account for these effects since general locomotor activity of BDNF- and vehicle-infused animals was not different. These findings demonstrate an antidepressant-like property of BDNF in two animal models of depression, which may be mediated by increased activity in monoaminergic systems.