Gainetdinov R R, Fumagalli F, Jones S R, Caron M G
Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.
J Neurochem. 1997 Sep;69(3):1322-5. doi: 10.1046/j.1471-4159.1997.69031322.x.
The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/- mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-/- mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/- mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.
在缺乏多巴胺（DA）转运体的小鼠（DAT-/-小鼠）身上测试了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的神经毒性作用。评估纹状体组织DA含量和胶质纤维酸性蛋白（GFAP）mRNA表达作为MPTP神经毒性的标志物。给药48小时后，MPTP（30mg/kg，皮下注射，每日两次）使野生型动物纹状体中的组织DA水平降低87%，GFAP mRNA水平升高29倍。相反，DAT-/-小鼠的这两个参数均无显著变化。杂合子对MPTP给药表现出部分敏感性，组织DA损失的中间值（48%）表明了这一点。通过微透析探针将MPTP的活性代谢产物1-甲基-4-苯基吡啶鎓（MPP+；10mM）直接纹状体内注入，在野生型小鼠中产生了大量的DA流出（>320倍）。在DAT-/-小鼠中，相同处理使细胞外DA的增加幅度小得多（六倍），这可能是由于植入透析探针导致组织损伤的继发结果。这些观察结果表明，DAT是MPTP在体内毒性表达的必需成分。
