Methamphetamine-induced selective dopaminergic neurotoxicity is accompanied by an increase in striatal nitrate in the mouse
Methamphetamine-induced selective dopaminergic neurotoxicity is accompanied by an increase in striatal nitrate in the mouse
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DOI：
10.1196/annals.1369.021
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Itzhak, Yossef
中科院分区：
文献类型：
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作者：
Anderson, Karen L.;Itzhak, Yossef
暴露于高剂量的甲基苯丙胺（一种主要的滥用药物）可能会导致神经元损伤。先前的研究表明，由一氧化氮（NO）和活性氧产生的过氧亚硝酸盐在甲基苯丙胺对小鼠产生的多巴胺能神经毒性中的作用。本文旨在研究甲基安非他明的神经毒性是否与一氧化氮稳定产物硝酸盐和亚硝酸盐的组织水平变化有关。给瑞士韦氏小鼠注射冰毒（5 mg/kg × 3）导致纹状体、杏仁核、额叶皮质和海马的5-羟色胺（5- ht）和5- ht转运体（5- htt）结合位点明显减少，提示冰毒对DA神经末段具有选择性神经毒性。注射甲基苯丙胺后，纹状体中硝酸盐浓度增加约2倍；然而，在遭受多巴胺能神经毒性的其他大脑区域，没有检测到硝酸盐浓度的变化。这些发现表明：(a)甲基苯丙胺的神经毒性方案可导致纹状体中NO的选择性增加，这可能产生有毒物质，如过氧亚硝酸盐；(b)非NO相关衍生物的毒素可能介导杏仁核和额叶皮层的多巴胺能神经毒性。
Exposure to high doses of methamphetamine (METH), a major drug of abuse, may cause neuronal damage. Previous studies have implicated the role of peroxynitrite, produced by nitric oxide (NO) and reactive oxygen species, in dopaminergic neurotoxicity produced by METH in mice. The present article was undertaken to investigate if a neurotoxic regimen of METH is associated with changes in tissue levels of nitrate and nitrite, which are the stable products of NO. Administration of METH (5 mg/kg x 3) to Swiss Webster mice resulted in marked depletion of dopamine (DA) and DA transporter (DAT) binding sites but no change in 5-hydroxytryptamine (5-HT) and 5-HT transporter (5-HTT) binding sites in the striatum, amygdala, frontal cortex, and hippocampus, suggesting that METH causes selective neurotoxicity to DA nerve terminals. The concentration of nitrate in the striatum was increased by about twofold after METH administration; however, no changes in nitrate concentration were detected in other brain regions that endured dopaminergic neurotoxicity. These findings suggest that (a) a neurotoxic regimen of METH produces selective increase in NO in the striatum, which may generate toxic species such as peroxynitrite, and (b) toxins other than NO-related derivatives may mediate dopaminergic neurotoxicity in the amygdala and frontal cortex.