Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

Abstract

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 decreasedIt has been shown that the female sex steroid estradiol exerts profound effects on neuronal differentiation during development (Toran-Allerand et al. 1983) and recently, accumulating evidence support also a modulatory role of estrogens in the normal maintenance of brain function during aging (Simpkins et al. 1994). Beneficial effects of estradiol in mood disorders (i.e., depression, pre-menstrual syndrome, post-natal depression), as well as mental diseases, such as schizophrenia and Gille de la Tourette's syndrome, have been reported (Di Paolo 1994;Fink et al. 1998). Moreover, a beneficial role of estradiol in neurodegenerative disFrom the Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, (CHUL), and Faculty of Pharmacy, Laval University, Sainte-Foy, Quebec, Canada, G1V 4G2.Address correspondence to: Dr. Thérèse Di Paolo, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, CHUQ, 2705, Laurier Boulevard, Sainte-Foy, Quebec, Canada G1V 4G2.Received July 5, 2000; revised December 20, 2000; accepted January 3, 2001. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 2 SERMs Modulate NMDA Receptors 243 eases, such as Alzheimer has been recently suggested (Tang et al. 1996;Henderson 1997;Inestrosa et al. 1998). However, the mechanisms by which these effects of estrogens are yet to be fully characterized. N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptor, have been implicated, as mediators, in some effects of estradiol on morphological plasticity and related physiological and cognitive processes in the brain (Moriyoshi et al. 1991). However, only few studies have directly investigated the role of estradiol in regulating NMDA receptors in rat and, in addition, these studies have focused on the effects of estradiol on hippocampal NMDA receptors (Woolley and McEwen 1992;Gazzaley et al. 1996;Woolley et al. 1997). We have recently investigated the effects of estradiol on the NMDA receptors agonist sites in brain regions implicated in mental disorders, such as frontal cortex, striatum, and nucleus accumbens (Cyr et al. 2000a). Our experiments showed that ovariectomy, as well as estradiol have regional specific effects since, for example, ovariectomy decreases NMDA receptor specific binding in hippocampal CA1 and dentate gyrus regions, whereas it has no effect in frontal cortex. In contrast, estradiol increases NMDA specific binding in the hippocampal CA1 and the dentate gyrus, but it decreases this binding in the frontal cortex (Cyr et al. 2000a).The present study sought to determine whether changes observed previously at the protein level after hormonal withdrawal due to ovariectomy or after estradiol treatment reflect changes at the level of gene transcription...

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

“…Along these lines, estrogen has been demonstrated to increase NMDA receptor binding [234,[299][300][301], increase NMDAR1 and NMDAR2b gene expression in CA1 region of the hippocampus of rats [302,303], and enhance NMDAdependent calcium signals in CA1 spines and dendrites [304]. Furthermore, NMDA receptor antagonists have been shown to block the estrogen-induced increase in spine density in the CA1 of the hippocampus [239,295,296].…”

Estradiol-Induced Increase in the Magnitude of Long-Term Potentiation Is Prevented by Blocking NR2B-Containing Receptors

“…Estradiol increases NR2B subunit mRNA, the number of NR2B binding sites, and the synaptic localization of NR2B-containing receptors (Cyr et al, 2001;Adams et al, 2004). It is currently unknown whether the estradiol-induced increase in NMDAR transmission is attributable to the increase in synaptic localization of NR2B-containing receptors.…”

“…It is currently unknown whether the estradiol-induced increase in NMDAR transmission is attributable to the increase in synaptic localization of NR2B-containing receptors. Furthermore, whether the increase in synaptic NR2B-containing receptors results from expression of new receptors or from lateral movement of existing receptors into the synapse is an open question (Cyr et al, 2001;Adams et al, 2004).…”

Maternal hypomagnesemia alters hippocampal NMDAR subunit expression and programs anxiety-like behaviour in adult offspring

“…Similarly, we also see sexual dimorphism in NMDAR expression which may be due in part to estrogen-mediated regulation of its subunits. Previous studies have demonstrated reduced NMDAR binding density and GluN1 and GluN2A expression in the hippocampus following ovariectomy, and reversal of this with estradiol treatment [39]. The ability of estrogen to enhance long-term potentiation at hippocampal synapses is also dependent on NMDARs [40].…”