Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
J Neurochem. 2010 Nov;115(3):595-605. doi: 10.1111/j.1471-4159.2010.06950.x. Epub 2010 Sep 6.
Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum.
甲基苯丙胺（METH）是一种神经毒性药物滥用，它以高度限定的方式损害多巴胺（DA）神经元系统。受 METH 影响最大的大脑结构是纹状体，那里的长期 DA 耗竭和小胶质细胞激活最大。内源性 DA 被认为是 METH 诱导的神经毒性的关键参与者，很可能是 METH 产生的活性氧非酶氧化的底物。纹状体也被 5-羟色胺（5HT）神经末梢广泛支配，这种神经化学系统在 DA 神经末梢中也以类似的方式被 METH 改变（即 5HT 释放增加、色氨酸羟化酶和 5HT 转运体功能丧失、5HT 储存长期耗竭）。5HT 也可以被活性氧物质修饰形成高度反应性的物质，从而损伤神经元，但它在 METH 神经毒性中的作用尚未得到评估。5-羟色氨酸增加 5HT 水平不会改变 METH 对 DA 神经末梢的神经毒性，因为 DA、酪氨酸羟化酶和多巴胺转运体水平降低。用对氯苯丙氨酸部分减少 5HT 对 METH 毒性没有影响，尽管对氯苯丙氨酸在很大程度上阻止了 METH 引起的发热。缺乏脑色氨酸羟化酶 2 基因的小鼠缺乏脑 5HT，并且对 METH 的反应与野生型对照相同，尽管它们表现出增强的药物诱导的发热。总之，目前的结果表明，内源性 5HT 似乎在 METH 诱导的纹状体 DA 神经末梢损伤中不起作用。
