Fumagalli F, Gainetdinov R R, Valenzano K J, Caron M G
Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Neurosci. 1998 Jul 1;18(13):4861-9. doi: 10.1523/JNEUROSCI.18-13-04861.1998.
The role of the dopamine transporter (DAT) in mediating the neurotoxic effects of methamphetamine (METH) was tested in mice lacking DAT. Dopamine (DA) and serotonin (5-HT) content, glial fibrillary acidic protein (GFAP) expression, and free radical formation were assessed as markers of METH neurotoxicity in the striatum and/or hippocampus of wild-type, heterozygote, and homozygote (DAT -/-) mice. Four injections of METH (15 mg/kg, s.c.), each given 2 hr apart, produced 80 and 30% decreases in striatal DA and 5-HT levels, respectively, in wild-type animals 2 d after administration. In addition, GFAP mRNA and protein expression levels, extracellular DA levels, and free radical formation were increased markedly. Hippocampal 5-HT content was decreased significantly as well (43%). Conversely, no significant changes were observed in total DA content, GFAP expression, extracellular DA levels, or free radical formation in the striatum of DAT -/- mice after METH administration. However, modest decreases were observed in striatal and hippocampal 5-HT levels (10 and 17%, respectively). These observations demonstrate that DAT is required for, and DA is an essential mediator of, METH-induced striatal dopaminergic neurotoxicity, whereas serotonergic deficits are only partially dependent on DAT.
在缺乏多巴胺转运体（DAT）的小鼠中测试了DAT在介导甲基苯丙胺（METH）神经毒性作用中的角色。评估了野生型、杂合子和纯合子（DAT -/-）小鼠纹状体和/或海马体中多巴胺（DA）和5-羟色胺（5-HT）含量、胶质纤维酸性蛋白（GFAP）表达以及自由基形成情况，以此作为METH神经毒性的标志物。给野生型动物皮下注射四次METH（15 mg/kg），每次间隔2小时，给药2天后，纹状体中DA和5-HT水平分别下降了80%和30%。此外，GFAP mRNA和蛋白表达水平、细胞外DA水平以及自由基形成均显著增加。海马体中5-HT含量也显著下降（43%）。相反，给DAT -/-小鼠注射METH后，纹状体中总DA含量、GFAP表达、细胞外DA水平或自由基形成均未观察到显著变化。然而，纹状体和海马体中5-HT水平出现了适度下降（分别为10%和17%）。这些观察结果表明，DAT是METH诱导的纹状体多巴胺能神经毒性所必需的，DA是其关键介质，而5-羟色胺能缺陷仅部分依赖于DAT。
