Hormonal specificity of modulation of N-methyl- D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreased uterine weight, which was prevented by a two-week estradiol treatment; tamoxifen and raloxifene had weaker uterine stimulation than estradiol. Ovariectomy in rats decreased L-[3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus but not CA2/3 regions of hippocampus and was without effect in cortex, striatum, nucleus accumbens, and olfactory tubercle. [3H]Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly) specific binding and mRNA levels of NMDA receptor subunits 1 and 2B decreased in CA1 after ovariectomy. Estradiol, tamoxifen, and raloxifene decreased L-[3H]glutamate specific binding to NMDA receptors and [3H]Ro 25-6981 specific binding in cortical area of ovariectomized rats and prevented the decrease of [3H]glutamate specific binding to NMDA receptors in CA1 and dentate gyrus, as well as [3H]Ro 25-6981 specific binding in CA1. Estradiol prevented the decrease of NMDA receptor subunits 1 and 2B mRNA levels in CA1 only; tamoxifen and raloxifene prevented the decrease of NMDA receptor subunit 1 mRNA levels in CA1. No effect of ovariectomy or treatments on L-[3H]CGP 39653 (an NMDA antagonist selective for NR1/NR2A assembly) specific binding and NMDA receptor subunit 2A mRNA levels was observed in all brain regions assayed. Our results showed brain regional and subunits specific agonist estrogenic activity of tamoxifen and raloxifene on NMDA receptors.