Adrenal steroids and N-methyl-D-aspartate receptor activation have both been shown to regulate the rate of proliferation of granule neuron progenitor cells in the dentate gyrus of adult rats [Cameron H. A. and Gould E. (1994) Neuroscience 61, 203-209; Cameron H. A. et al. (1995) J. Neurosci. 15, 46874692]. Parallels between the actions of these two factors suggest that they may regulate cell division through a common pathway. This hypothesis was tested by altering both of the factors simultaneously and determining whether the effects were additive. The results of this study demonstrate that alterations in N-methyl-D-aspartate receptor activation block the effects of corticosterone level on cell proliferation; N-methyl-D-aspartate blocks the adrenalectomy-induced increase in [3H]thymidine-labelled cell density in the dentate gyrus, whereas the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (MK-801) prevents the corticosterone-induced decrease in proliferating cells. This finding suggests that adrenal steroids and N-methyl-D-aspartate receptor activation regulate granule cell production in the adult rat dentate gyrus through a common pathway and that N-methyl-D-aspartate receptor activation operates downstream of corticosterone in this pathway.