N-methyl-D-aspartate receptor activity and estradiol: separate regulation of cell proliferation in the dentate gyrus of adult female meadow vole.

We have previously found that estradiol increases (within 4 h) but then decreases (within 48 h) cell proliferation in the dentate gyrus of adult female ovariectomized (OVX) rats and of intact meadow voles and that estradiol partially stimulates adrenal activity to suppress cell proliferation in rats. Estradiol enhances N-methyl-D-aspartate receptor (NMDAr) activity and NMDAr activation suppresses cell proliferation in the adult rodent dentate gyrus. Therefore, we tested whether estradiol alters cell proliferation in the dentate gyrus of adult OVX female meadow voles by stimulating NMDAr activity. In experiment 1, OVX females were injected with estradiol (10 micro g) or oil and then with NMDA (30 mg/kg) or vehicle 3 h later and bromodeoxyuridine 4 h later (BrdU; 50 mg/kg). Voles were perfused 1 h after BrdU injection. Relative to oil vehicle, estradiol increased (P</=0.001) and NMDA decreased (P</=0.006) labeled cell number. Coadministration of estradiol/NMDA increased labeled cell numbers relative to NMDA alone (P</=0.03), suggesting that within 4 h estradiol does not influence the effect of NMDA receptors on cell proliferation. In experiment 2, OVX females were injected with either estradiol or oil and then with either MK-801 (1 mg/kg) or vehicle 47 h later and BrdU 48 h later. The animals were perfused 1 h after BrdU was injected. Relative to oil-treated voles, estradiol-treated voles had fewer (P<0.006) and MK-801-treated voles had more labeled cells (P</=0.0001) in the dentate gyrus. However, estradiol did not appear to stimulate NMDA receptors to suppress cell proliferation because estradiol (48 h)/MK-801-treated voles had fewer BrdU-labeled cells than oil (48 h)/MK-801-treated voles (P</=0.06). The results show that estradiol time-dependently influences cell proliferation but that estradiol does not stimulate NMDAr activity to influence cell proliferation in the dentate gyrus of adult voles.