Methamphetamine Administration Causes Death of Dopaminergic Neurons in the Mouse

背景：甲基苯丙胺（Methamphetamine，简称冰毒）是一种能引起神经和精神疾病的成瘾性药物。在啮齿类动物的大脑中，毒剂量的甲基苯丙胺引起多巴胺能末端的损伤和非多巴胺能神经元的凋亡。嗅球（OB）是大脑中富含多巴胺能神经元和终末的区域。方法：大鼠单次注射冰毒（40 mg/kg），在不同时间点处死。通过测定单胺水平、酪氨酸羟化酶（TH）免疫细胞化学、末端脱氧核苷酸转移酶介导的脱氧核糖核苷酸三磷酸（dNTP）缺口末端标记（TUNEL）组织化学和caspase-3免疫化学来评估该注射液对OB的毒性作用。结果：甲基苯丙胺给药导致小鼠OB中多巴胺（DA）水平和TH样免疫染色明显降低，药物还导致tunel标记的OB神经元增加，其中部分神经元TH表达阳性。此外，th阳性细胞中有meth诱导的活化caspase-3表达。最后，注射甲基安非他明可增加促凋亡蛋白Bax和Bid的表达，但降低抗死亡蛋白Bcl2的表达。结论：这些观察结果首次表明，甲基安非他明可导致OB - DA终末丢失和DA神经元死亡，其部分机制类似于细胞凋亡过程。

BACKGROUND: Methamphetamine (METH) is an addictive drug that can cause neurological and psychiatric disorders. In the rodent brain, toxic doses of METH cause damage of dopaminergic terminals and apoptosis of nondopaminergic neurons. The olfactory bulb (OB) is a brain region that is rich with dopaminergic neurons and terminals. METHODS: Rats were given a single injection of METH (40 mg/kg) and sacrificed at various time points afterward. The toxic effects of this injection on the OB were assessed by measuring monoamine levels, tyrosine hydroxylase (TH) immunocytochemistry, terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL) histochemistry, and caspase-3 immunochemistry. RESULTS: Methamphetamine administration caused marked decreases in dopamine (DA) levels and TH-like immunostaining in the mouse OB. The drug also caused increases in TUNEL-labeled OB neurons, some of which were also positive for TH expression. Moreover, there was METH-induced expression of activated caspase-3 in TH-positive cells. Finally, the METH injection was associated with increased expression of the proapoptotic proteins, Bax and Bid, but with decreased expression of the antideath protein, Bcl2. CONCLUSIONS: These observations show, for the first time, that METH can cause loss of OB DA terminals and death of DA neurons, in part, via mechanisms that are akin to an apoptotic process.