Characterizing the mechanisms by which endogenous factors stimulate neurogenesis is of special interest in view of the possible implication of newly generated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5-HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long-lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5-HT synthesis using p-chlorophenylalanine (PCPA) treatment produced approximately the same decreases in the number of bromodeoxyuridine (BrdU) and PSA-NCAM immunolabelled cells in the subgranular layer as ovariectomy alone. Administration of 5-hydroxytryptophan (5-HTP) restored cell proliferation primarily decreased by ovariectomy, whereas oestradiol was unable to reverse this change in ovariectomized rats treated with PCPA. These findings demonstrate that 5-HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomitant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5-HT and oestradiol. Finally, oestrogen may regulate structural plasticity by stimulating PSA-NCAM expression independently of neurogenesis, as shown for instance by the increases in the number of PSA-NCAM labelled cells in pregnants. As 5-HT and oestrogen are involved in mood disorders, our data suggest that the positive regulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.