Influence of oestrogenic compounds on monoamine transporters in rat striatum.
Oestrogens have been reported to modulate rat membrane (DAT) and vesicular (VMAT(2)) dopamine transporters. A recent pilot study of postmenopausal women showed that chronic oestrogen replacement therapy increases striatal DAT. In the present study, we first investigated whether the oestrogen receptors alpha and beta mediate the effects of oestradiol on DAT and VMAT(2). Two days after ovariectomy, Sprague-Dawley rats were treated for 2 weeks with oestradiol or specific ligands for oestrogen receptor alpha, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) or oestrogen receptor beta, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN). Ovariectomy caused a decrease in [(125)I]-3beta-(4-iodophenyl)-tropane-2beta-carboxylic acid isopropyl ester ([(125)I] RTI-121) specific binding to DAT transporters in the middle striatum compared to values for intact rats, and this was reversed by oestradiol replacement therapy. DPN, but not PPT, mimicked the effect of oestradiol. [(125)I] RTI-121 specific binding in the anterior and posterior striatum was not affected by ovariectomy or any of the drug treatments. Second, we investigated whether oestradiol increased DAT specific binding after a longer period of hormonal withdrawal (a model of hormonal withdrawal at menopause) and whether the selective oestrogen receptor modulators (SERMs), tamoxifen and raloxifene, could reproduce the oestradiol-induced increase of [(125)I] RTI-121 specific binding in long-term ovariectomised rats. Four months after ovariectomy, Sprague-Dawley rats were treated for 2 weeks with oestradiol, tamoxifen or raloxifene, and then killed. Ovariectomy decreased [(3)H] RTI-121 specific binding to DAT transporters in the middle striatum compared to values for intact rats. Treatment with oestradiol, tamoxifen and raloxifene reversed this effect. [(125)I] RTI-121 specific binding in anterior and posterior striatum was not affected by ovariectomy or treatment with oestrogen receptor ligands. In both experiments, neither ovariectomy nor the oestrogenic treatments modulated striatal [(3)H] tetrahydrobenazine specific binding to VMAT(2). Overall, these results suggest that oestrogen receptor beta mediates the oestradiol-induced increase of striatal DAT and that oestradiol can increase DAT density even after long-term steroid withdrawal. The results also support the premise that the SERMs tamoxifen and raloxifene exert oestrogenic agonist effects in the brain.
Le Saux
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Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL) and Faculté de Pharmacie, Université Laval, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
Di Paolo
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T
D000704:Analysis of Variance; D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D017072:Neostriatum / Q000378:metabolism*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D050493:Vesicular Monoamine Transport Proteins; D004958:Estradiol