Albers D S, Zeevalk G D, Sonsalla P K
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854, USA.
Brain Res. 1996 Apr 29;718(1-2):217-20. doi: 10.1016/0006-8993(96)00135-7.
The mechanisms involved in methamphetamine (METH)-induced damage to nigrostriatal dopaminergic neurons in experimental animals are unknown. We have examined the possibility that perturbations in energy metabolism contribute to METH-induced toxicity by investigating the effects of systemic METH treatment in mice which received a unilateral intrastriatal infusion of malonate, a metabolic inhibitor which decreases ATP levels. Malonate (1-4 mumol) produced a dose-dependent decrease in striatal dopamine (DA). The combined treatment of intrastriatal malonate with systemic METH resulted in greater damage to dopaminergic neurons than by METH or malonate treatment alone. In parallel studies, MPTP was administered to mice which received intrastriatal infusions of saline or malonate. Similar to results obtained with METH, decreases in striatal DA content and tyrosine hydroxylase (TH) activity were greatest in MPTP-treated mice infused with malonate. The present results lend credence to the hypothesis that METH-induced increases in energy utilization create a state of metabolic stress for DA neurons which may ultimately contribute to the neurodegenerative effects of METH. Moreover, the finding that combined malonate and MPTP treatment produced greater damage than either substance alone is consistent with the hypothesis that perturbations in energy metabolism contribute to the neuronal death produced by MPP+.
甲基苯丙胺（METH）对实验动物黑质纹状体多巴胺能神经元造成损伤的机制尚不清楚。我们通过研究全身性METH处理对接受单侧纹状体内注入丙二酸（一种降低ATP水平的代谢抑制剂）的小鼠的影响，来检验能量代谢紊乱是否会导致METH诱导的毒性。丙二酸（1 - 4 μmol）使纹状体多巴胺（DA）呈剂量依赖性降低。纹状体内丙二酸与全身性METH联合处理对多巴胺能神经元造成的损伤比单独使用METH或丙二酸处理更大。在平行研究中，给接受纹状体内注入生理盐水或丙二酸的小鼠施用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。与METH处理的结果相似，在注入丙二酸的MPTP处理小鼠中，纹状体DA含量和酪氨酸羟化酶（TH）活性的降低最为显著。目前的结果支持了这样一种假说，即METH诱导的能量利用增加为DA神经元创造了一种代谢应激状态，这最终可能导致METH的神经退行性作用。此外，丙二酸和MPTP联合处理比单独使用任何一种物质造成更大损伤这一发现，与能量代谢紊乱导致MPP⁺引起神经元死亡的假说一致。
