The fibroblast growth factor (FGF) system is altered in post-mortem brains of individuals with major depressive disorder (MDD), but the functional relevance of this observation remains to be elucidated. To this end, we tested whether administering agents that act on FGF receptors would have antidepressant-like effects in rodents. We microinjected either FGF2 (200 ng, i.c.v.) or the FG loop (FGL) of neural cell adhesion molecule (NCAM) (5 microg, i.c.v.) into the lateral ventricle of rats and tested them on the forced swim test. Activating FGF receptors acutely had an antidepressant-like effect in the forced swim test. Furthermore, chronic FGF2 decreased depression-like behavior as assessed by two independent tests. Finally, the FGF system itself was altered after FGF2 administration. Specifically, there was an increase in FGFR1 mRNA in the dentate gyrus 24 h post-FGF2, suggesting the potential for self-amplification of the initial signal. These results support the potential therapeutic use of FGF2 or related molecules in the treatment of MDD and point to alternate mechanisms of neuronal remodeling that may be critical in this treatment.