Le Saux M, Di Paolo T
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.
J Neuroendocrinol. 2006 Jan;18(1):25-32. doi: 10.1111/j.1365-2826.2005.01380.x.
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.
据报道，雌激素可调节大鼠的膜（多巴胺转运体，DAT）和囊泡（囊泡单胺转运体2，VMAT(2)）多巴胺转运蛋白。最近一项针对绝经后女性的初步研究表明，长期雌激素替代疗法可增加纹状体DAT。在本研究中，我们首先研究了雌激素受体α和β是否介导雌二醇对DAT和VMAT(2)的作用。在卵巢切除术后两天，对Sprague-Dawley大鼠用雌二醇或雌激素受体α的特异性配体4,4',4''-(4-丙基-[1H]-吡唑-1,3,5-三基)三苯酚（PPT）或雌激素受体β的特异性配体2,3-双(4-羟基苯基)-丙腈（DPN）进行为期2周的治疗。与完整大鼠相比，卵巢切除术导致[(125)I]-3β-(4-碘苯基)-托烷-2β-羧酸异丙酯（[(125)I]RTI-121）与纹状体中部DAT转运蛋白的特异性结合减少，而雌二醇替代疗法可逆转这种情况。DPN可模拟雌二醇的作用，但PPT不能。[(125)I]RTI-121在前纹状体和后纹状体的特异性结合不受卵巢切除术或任何药物治疗的影响。其次，我们研究了在更长时间的激素撤药后（绝经后激素撤药模型）雌二醇是否会增加DAT特异性结合，以及选择性雌激素受体调节剂（SERM）他莫昔芬和雷洛昔芬是否能在长期卵巢切除的大鼠中重现雌二醇诱导的[(125)I]RTI-121特异性结合增加。卵巢切除术后四个月，对Sprague-Dawley大鼠用雌二醇、他莫昔芬或雷洛昔芬进行为期2周的治疗，然后处死。与完整大鼠相比，卵巢切除术降低了[(3)H]RTI-121与纹状体中部DAT转运蛋白的特异性结合。用雌二醇、他莫昔芬和雷洛昔芬治疗可逆转这种作用。[(125)I]RTI-121在前纹状体和后纹状体的特异性结合不受卵巢切除术或雌激素受体配体治疗的影响。在两个实验中，卵巢切除术和雌激素治疗均未调节纹状体[(3)H]四氢苯嗪与VMAT(2)的特异性结合。总体而言，这些结果表明雌激素受体β介导了雌二醇诱导的纹状体DAT增加，并且即使在长期类固醇撤药后雌二醇仍可增加DAT密度。结果还支持SERM他莫昔芬和雷洛昔芬在大脑中发挥雌激素激动剂作用这一前提。
