Regional and Selective Effects of Oestradiol and Progesterone on NMDA and AMPA Receptors in the Rat Brain

Abstract

We investigated the effect of 10 months ovariectomy and a correction therapy, 2 weeks before the rats were killed, of oestradiol, progesterone or their combination on NMDA and AMPA receptor binding in the hippocampus, dentate gyrus, striatum, nucleus accumbens and frontal cortex of the rat brain as well as on amino acid levels in frontal cortex. NMDA and AMPA binding densities were assayed by autoradiography using, respectively, L-[3H]glutamate and [3H]AMPA; amino acid concentrations were measured by high performance liquid chromatograhy (HPLC) coupled with UV detection. Ovariectomy was without effect on NMDA and AMPA binding density in all brain regions assayed except in the hippocampal CA1 region and dentate gyrus where it decreased NMDA binding density compared to intact rats values. Oestradiol restored and increased NMDA binding density in the CA1 subfield and the dentate gyrus of ovariectomized rats but, by contrast, it decreased binding density in the striatum and in the frontal cortex while having no effect in the CA2/3 subfield of the hippocampus and in the nucleus accumbens. Oestradiol was without effect on AMPA binding density in the hippocampus and the dentate gyrus but it reduced AMPA binding density in the striatum, the frontal cortex and the nucleus accumbens. Progesterone, and oestradiol combined with progesterone, decreased NMDA but not AMPA binding density in the frontal cortex of ovariectomized rats, and they were without effect on these receptors in the other brain regions assayed. Amino acid concentrations in the frontal cortex were unchanged after ovariectomy or steroid treatments. The effect of oestradiol in the hippocampus confirmed in the present study and our novel findings in the frontal cortex, striatum and nucleus accumbens may have functional significance for schizophrenia and neurodegenerative diseases.

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

“…Our experiments showed that two weeks replacement therapy with estradiol decreased L-[ 3 H]glutamate specific binding in cingulate cortex, but not in the frontal or the parietal cortices. This confirms the regional specificity in the brain of estradiol on glutamate receptors that we previously reported (Cyr et al 2000a) and further refines the effect in the rostral cortex which is mostly in the cingulate cortex. NMDA receptors and L-[ 3 H]glutamate specific binding displayed a parallel pattern of changes after ovariectomy and estradiol treatment in the cingulate cortex, suggesting that the NMDA receptor is one of the glutamate receptor subtypes implicated in the hormonal modulation of L-[ 3 H]glutamate specific binding.…”

“…NMDA receptors and L-[ 3 H]glutamate specific binding displayed a parallel pattern of changes after ovariectomy and estradiol treatment in the cingulate cortex, suggesting that the NMDA receptor is one of the glutamate receptor subtypes implicated in the hormonal modulation of L-[ 3 H]glutamate specific binding. We have previously found a parallel pattern of changes in NMDA receptors and L-[ 3 H]glutamate specific binding in the cortical regions after ovariectomy and estradiol treatment (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). …”

“…Autoradiography of glutamate and NMDA receptor agonist sites using L-[ 3 H]glutamate was performed as previously described (Cyr et al 2000a). Slide-mounted brains sections were preincubated for 10 min at 30 Њ C in the incubation buffer: 50 mM Tris-Acetate, pH 7.2.…”

“…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.…”