Effect of Oestrogen Receptor Alpha and Beta Agonists on BrainN-Methyl-d-Aspartate Receptors

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Abstract
Previous studies have shown the oestradiol modulation of brain N-methyl-D-aspartate (NMDA) receptors composed of the NR1/2B subunits. The contribution of oestrogen receptor subtypes in this oestradiol modulation of NMDA receptors and its subunits is not known. The following experiments investigated whether an oestrogenic receptor subtype is involved in the oestradiol effect on NMDA receptor specific binding and subunit mRNA levels. Ovariectomised Sprague-Dawley rats were treated 2 days after ovariectomy for 2 weeks with 17beta-oestradiol, an agonist for oestrogen receptor (ER)alpha 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or an agonist for ER beta 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) and compared with control vehicle-treated ovariectomised and intact rats. Uterus weights, used as a peripheral measure of oestrogenic activity, decreased after ovariectomy and increased by oestradiol and PPT but not DPN treatment. In the hippocampal CA1 oriens and CA1 radiatum, [(3)H]Ro 25-6981 specific binding, a NMDA/NR2B ligand, was decreased in ovariectomised compared to intact rats and this was prevented by 17beta-oestradiol or PPT but not DPN treatments; a similar pattern was observed in the CA2/3 and dentate gyrus but did not reach statistical significance. In situ hybridisation of the mRNA of the NMDA/2B subunit in the hippocampus CA1, CA2/3 and dentate gyrus showed a decrease in ovariectomised rats compared to controls and this was also prevented by 17beta-oestradiol and PPT but not DPN treatments. In cingulate and prefrontal cortices, ovariectomy increased [(3)H]Ro 25-6981 specific binding compared to intact controls, which was corrected by 17beta-oestradiol treatment but neither by PPT, nor DPN. In the cortical regions, the lack of effect of the ER alpha or ER beta agonist whereas 17beta-oestradiol was active, suggesting that the oestradiol modulation of cortical NMDA receptors requires both ERs or that this modulation does not involve ERs. In the hippocampus, the results obtained suggest an oestrogenic genomic modulation of NMDA receptors containing the NR2B subunit, implicating an ER alpha.

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