Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Bethesda, Maryland, United States of America.
PLoS One. 2011 Apr 25;6(4):e19179. doi: 10.1371/journal.pone.0019179.
Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.
甲基苯丙胺（METH）是一种在美国和全球范围内广泛滥用的成瘾性和神经毒性精神兴奋剂。当大剂量使用时，METH 可导致纹状体多巴胺末梢耗竭，而中脑多巴胺能神经元得以保留。由于调节多巴胺能神经元发育的转录因子表达的改变可能与保护这些神经元免受毒性损伤有关，因此我们测试了这些因子的表达是否可能受到成年大脑中有毒剂量 METH 的影响。先用生理盐水或递增剂量的 METH 预处理雄性 Sprague-Dawley 大鼠，然后用有毒剂量的药物进行挑战，两周后处死。接受有毒 METH 挑战的动物表现出纹状体多巴胺水平降低和酪氨酸羟化酶蛋白浓度降低。METH 预处理可防止纹状体多巴胺和酪氨酸羟化酶的丢失。相反，METH 挑战导致生理盐水和 METH 预处理动物的多巴胺转运体减少。有趣的是，METH 挑战在存在 METH 预处理的情况下引起中脑多巴胺转运体 mRNA 水平的增加，但在不存在 METH 预处理的情况下则没有。此外，有毒的 METH 剂量导致生理盐水预处理大鼠中多巴胺发育因子 Shh、Lmx1b 和 Nurr1 的表达减少，但 Otx2 和 Pitx3 的水平不变。METH 预处理后再用 METH 进行挑战也会降低中脑的 Nurr1 表达，但会增加 Otx2 和 Pitx3 的表达。这些发现表明，在成年动物中，有毒剂量的 METH 可能会以不同的方式影响参与多巴胺神经元发育调节的转录因子的表达。METH 预处理后 Otx2 和 Pitx3 表达的联合增加可能部分代表了一些机制，这些机制有助于防止 METH 预处理后观察到的 METH 诱导的纹状体多巴胺耗竭。
