Melatonin, involved in circadian cycle, provides protective effects on neuronal cells and acts as antidepressant by restoration of corticosterone levels. A mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone treatment, has been used to evaluate behavior and adult hippocampal neurogenesis in mice and their possible modulation under melatonin. With this aim, CD1 mice were subjected to 7 wk of corticosterone administration, and then behavioral tests as novelty-suppressed feeding, open field and a forced swim test were performed. Cell proliferation in hippocampal dentate gyrus (DG) was investigated by 5-bromo-2'-deoxyuridine and doublecortin immunohistochemistry techniques, and stereological procedure was used to quantify labeled cells. Golgi-impregnated method was used to evaluate the changes of dendritic spines in DG neurons. A new therapeutic approach with antidepressant-like substances (3 wk) such as melatonin (8 mg/kg) was employed to possibly modulate neural development in the adult hippocampus and the behavioral changes. The depressive-like state caused by chronic corticosterone treatment was reversed by exogenous administration of melatonin; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment (cort- 83.7 +/- 20.3 versus cort+ 60.5 +/- 18.2; P < 0.05), whereas long-term treatment with melatonin prevented the corticosterone-induced reduction in hippocampal cell proliferation (cort- 60.5 +/- 18.2 versus mel 133.4 +/- 26.9; P < 0.05). Corticosterone-treated mice exhibited a reduced spine density, which was ameliorated by melatonin administration. These findings suggest a strong correspondence between behavior and neurogenesis, strengthening the hypothesis that neurogenesis contributes to the effects of melatonin as an antidepressant.