Methamphetamine Administration Causes Death of Dopaminergic Neurons in the Mouse

背景：甲基苯丙胺是一种成瘾药物，可导致神经和精神障碍。在啮齿类动物的大脑中，中毒剂量的冰毒可导致多巴胺能终末的损伤和非多巴胺能神经元的凋亡。嗅球是一个富含多巴胺能神经元和终末的大脑区域。方法：大鼠一次性注射冰毒(40 mg/kg)后，于不同时间点处死。通过单胺水平、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酸三磷酸(DNTP)缺口末端标记(TUNEL)组织化学和半胱氨酸天冬氨酸氨基转移酶-3(caspase-3)免疫组织化学方法评价其对OB的毒性作用。结果：甲基苯丙胺可显著降低小鼠OB的多巴胺(DA)水平和TH样免疫反应。该药物还导致TUNEL标记的OB神经元增加，其中一些神经元TH表达也呈阳性。此外，冰毒诱导TH阳性细胞表达活化的caspase-3。最后，冰毒注射与促凋亡蛋白Bax和Bid的表达增加有关，但与抗死亡蛋白Bcl2的表达减少有关。结论：这些观察首次表明，冰毒可以导致OB DA终末的丢失和DA神经元的死亡，部分是通过类似于细胞凋亡过程的机制。

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.