Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining
Methamphetamine Causes Degeneration of Dopamine Cell Bodies and Terminals of the Nigrostriatal Pathway Evidenced by Silver Staining
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DOI：
10.1038/npp.2013.307
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发表时间：
2014-04-01
影响因子：
7.6
通讯作者：
Moratalla, Rosario
中科院分区：
文献类型：
--
作者：
Ares-Santos, Sara;Granado, Noelia;Moratalla, Rosario
甲基苯丙胺是一种广泛滥用的非法药物。最近的流行病学研究表明，甲基苯丙胺会增加患帕金森病（PD）的风险，这与动物研究显示的多巴胺能神经毒性一致。我们研究了重复低剂量和中等剂量与单次高剂量甲基苯丙胺对多巴胺能末梢和细胞体变性的影响。以以下范例之一给予小鼠甲基苯丙胺：以3小时间隔注射3次5或10 mg/kg或单次注射30 mg/kg。通过酪氨酸羟化酶免疫组织化学和银染色，在甲基苯丙胺后的不同时间点评估多巴胺能纤维和细胞体的完整性。3 x 10方案产生纹状体多巴胺能终末的最高损失，其次是3 x 5和1 x 30。从纹状体到黑质部的神经元中可追踪到一些退化的轴突。所有.通过氨基-铜-银染色的多巴胺能神经元证明，方案诱导了SNpc中多巴胺能神经元的类似显著变性。这些神经元以坏死和凋亡的方式死亡。甲基苯丙胺也会杀死纹状体神经元。通过使用D1-Tmt/D2-GFP BAC转基因小鼠，我们观察到退化的纹状体神经元均匀地分布在直接和间接的中棘神经元之间。尽管治疗后30天SNPC中多巴胺能神经元的数量减少，但治疗后3天开始多巴胺终末部分时间依赖性恢复。治疗后1-3天，自发活动和运动协调性显著降低，但沿着多巴胺能末梢恢复。这些数据提供了直接证据，甲基苯丙胺导致SNpc中多巴胺能细胞体的长期损失/变性，沿着纹状体中多巴胺能末梢的破坏。
Methamphetamine is a widely abused illicit drug. Recent epidemiological studies showed that methamphetamine increases the risk for developing Parkinson's disease (PD) in agreement with animal studies showing dopaminergic neurotoxicity. We examined the effect of repeated low and medium doses vs single high dose of methamphetamine on degeneration of dopaminergic terminals and cell bodies. Mice were given methamphetamine in one of the following paradigms: three injections of 5 or I 0 mg/kg at 3 h intervals or a single 30 mg/kg injection. The integrity of dopaminergic fibers and cell bodies was assessed at different time points after methamphetamine by tyrosine hydroxylase immunohistochemistry and silver staining. The 3 x 10 protocol yielded the highest loss of striatal dopaminergic terminals, followed by the 3 x 5 and 1 x 30. Some degenerating axons could be followed from the striatum to the substantia nigra pars compacta (SNpc). All. protocols induced similar significant degeneration of dopaminergic neurons in the SNpc, evidenced by amino-cupric-silver-stained dopaminergic neurons. These neurons died by necrosis and apoptosis. Methamphetamine also killed striatal neurons. By using D1-Tmt/D2-GFP BAC transgenic mice, we observed that degenerating striatal neurons were equally distributed between direct and indirect medium spiny neurons. Despite the reduced number of dopaminergic neurons in the SNpc at 30 days after treatment, there was a partial time-dependent recovery of dopamine terminals beginning 3 days after treatment. Locomotor activity and motor coordination were robustly decreased 1-3 days after treatment, but recovered at later times along with dopaminergic terminals. These data provide direct evidence that methamphetamine causes long-lasting loss/degeneration of dopaminergic cell bodies in the SNpc, along with destruction of dopaminergic terminals in the striatum.