Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice
Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice
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DOI：
10.1111/j.1471-4159.2008.05705.x
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发表时间：
2008-11-01
影响因子：
4.7
通讯作者：
Moratalla, Rosario
中科院分区：
文献类型：
--
作者：
Granado, Noelia;O'Shea, Esther;Moratalla, Rosario
急性给药重复剂量的3，4-亚甲基二氧基甲基苯丙胺（摇头丸，摇头丸）显着降低纹状体多巴胺（DA）含量，酪氨酸羟化酶（TH），和DA转运蛋白免疫反应性的小鼠。在这项研究中，我们第一次展示了MDMA给药小鼠产生的多巴胺能损伤和相关分子事件的时空模式。我们的研究结果包括新的发现，MDMA产生的TH-免疫反应神经元在黑质（SN）的数量显着减少。这种减少出现在注射后1天，保持稳定至少30天，并伴随着剂量依赖性的长期减少TH和DA转运蛋白的免疫反应性在纹状体，达到峰值后1天的治疗，并持续至少30天，然而，一些恢复是明显的，从第3天开始，证明发芽TH纤维。NAc没有观察到变化，表明MDMA导致黑质纹状体通路中含DA神经元的选择性破坏，保留了中脑边缘通路。MDMA处理后1天Mac-1表达增加，处理后3天纹状体和SN中的胶质细胞酸性蛋白表达增加，但NAc中没有，与多巴胺能损伤严格相关。这些数据提供了MDMA导致SN中多巴胺能细胞体持续丢失的第一个证据。
Acute administration of repeated doses of 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) dramatically reduces striatal dopamine (DA) content, tyrosine hydroxylase (TH), and DA transporter-immunoreactivity in mice. In this study, we show for the first time the spatiotemporal pattern of dopaminergic damage and related molecular events produced by MDMA administration in mice. Our results include the novel finding that MDMA produces a significant decrease in the number of TH-immunoreactive neurons in the substantia nigra (SN). This decrease appears 1 day after injection, remains stable for at least 30 days, and is accompanied by a dose-dependent long-lasting decrease in TH- and DA transporter-immunoreactivity in the striatum, which peaked 1 day after treatment and persisted for at least 30 days, however, some recovery was evident from day 3 onwards, evidencing sprouting of TH fibers. No change is observed in the NAc indicating that MDMA causes selective destruction of DA-containing neurons in the nigrostriatal pathway, sparing the mesolimbic pathway. The expression of Mac-1 increased 1 day after MDMA treatment and glial fibrillary acidic protein increased 3 days post-treatment in the striatum and SN but not in the NAc, in strict anatomical correlation with dopaminergic damage. These data provide the first evidence that MDMA causes persistent loss of dopaminergic cell bodies in the SN.