Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity.
Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity.
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DOI：
10.1016/j.neuroscience.2011.09.014
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发表时间：
2011-12-29
期刊：
影响因子：
3.3
通讯作者：
Marshall, J. F.
中科院分区：
文献类型：
--
作者：
Gross, N. B.;Duncker, P. C.;Marshall, J. F.
精神兴奋剂药物甲基苯丙胺（mAMPH）的大量使用会在纹状体产生长期的结构和功能异常。mAMPH狂欢产生多巴胺（DA）的非胞吐释放，并且mAMPH诱导的兴奋性传入输入到皮质和纹状体的激活通过两个区域中升高的细胞外谷氨酸（GLU）来证明。认为mAMPH诱导的DA和GLU神经传递的增加联合收割机损伤暴露于mAMPH的脑的纹状体DA神经末梢。竞争性或非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂的全身预处理可保护mAMPH诱导的纹状体DA末端损伤，但这些拮抗剂的作用部位尚未确定。在这里，我们应用NMDA受体拮抗剂，（DL）-氨基-5-膦酰基戊酸（AP 5），或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂，二硝基喹喔啉-2，3-二酮（DNQX），直接到硬脑膜额顶叶皮层，以评估其对mAMPH诱导的皮质和纹状体的即刻早期基因（c-fos）表达的影响。在另一项实验中，我们在mAMPH的狂欢方案期间将AP 5或DNQX在大鼠的相同皮层位置中进行了模拟应用，并在一周后评估了mAMPH诱导的纹状体多巴胺转运蛋白（DAT）消耗。我们的研究结果表明，这两种离子型谷氨酸受体拮抗剂减少了mAMPH诱导的Fos的表达，在大脑皮层区域附近的硬膜外应用程序和减少Fos免疫反应受影响的皮层区域支配的纹状体区域。此外，硬膜外应用相同浓度的任一拮抗剂在一个狂欢mAMPH方案钝化mAMPH诱导的纹状体DAT耗尽的地形类似于其对Fos表达的影响。这些研究结果表明，mAMPH诱导的多巴胺能损伤依赖于皮层NMDA和AMPA受体的激活，并建议参与mAMPH神经毒性的皮质纹状体的预测。
Binge administration of the psychostimulant drug, methamphetamine (mAMPH), produces long-lasting structural and functional abnormalities in the striatum. mAMPH binges produce non-exocytotic release of dopamine (DA), and mAMPH-induced activation of excitatory afferent inputs to cortex and striatum is evidenced by elevated extracellular glutamate (GLU) in both regions. The mAMPH-induced increases in DA and GLU neurotransmission are thought to combine to injure striatal DA nerve terminals of mAMPH-exposed brains. Systemic pretreatment with either competitive or noncompetitive N-methyl-D-aspartic acid (NMDA) antagonists protects against mAMPH-induced striatal DA terminal damage, but the locus of these antagonists’ effects has not been determined. Here, we applied either the NMDA receptor antagonist, (DL)-amino-5-phosphonovaleric acid (AP5), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, dinitroquinoxaline-2,3-dione (DNQX), directly to the dura mater over frontoparietal cortex to assess their effects on mAMPH-induced cortical and striatal immediate-early gene (c-fos) expression. In a separate experiment we applied AP5 or DNQX epidurally in the same cortical location of rats during a binge regimen of mAMPH, and assessed mAMPH-induced striatal dopamine transporter (DAT) depletions one week later. Our results indicate that both ionotropic glutamate receptor antagonists reduced the mAMPH-induced Fos expression in cerebral cortex regions near the site of epidural application and reduced Fos immunoreactivity in striatal regions innervated by the affected cortical regions. Also, epidural application of the same concentration of either antagonist during a binge mAMPH regimen blunted the mAMPH-induced striatal DAT depletions with a topography similar to its effects on Fos expression. These findings demonstrate that mAMPH-induced dopaminergic injury depends upon cortical NMDA and AMPA receptor activation and suggest the involvement of the corticostriatal projections in mAMPH neurotoxicity.
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影响因子：
7.6
作者：
Belcher, AM;O'Dell, SJ;Marshall, JF
通讯作者：
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