Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice
Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice
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DOI：
10.1523/jneurosci.1067-07.2007
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发表时间：
2007-08-15
影响因子：
5.3
通讯作者：
McGinty, Jacqueline F.
中科院分区：
文献类型：
--
作者：
Boger, Heather A.;Middaugh, Lawrence D.;McGinty, Jacqueline F.
年轻人滥用甲基苯丙胺对脑功能有长期的有害影响，与单胺能神经元的损伤有关。胶质细胞源性神经营养因子（GDNF）在动物模型中保护多巴胺神经元免受甲基苯丙胺的毒性作用。因此，我们假设部分GDNF基因缺失会增加小鼠在年轻成年期对甲基苯丙胺神经毒性的易感性，并可能增加与年龄相关的行为和多巴胺功能恶化。甲基苯丙胺狂欢（4 x 10 mg/kg，i. p.，间隔2小时），与野生型小鼠相比，GDNF（+/）-小鼠在内侧纹状体中具有显著更大的酪氨酸羟化酶免疫反应性降低，纹状体中多巴胺和3，4-二羟基苯乙酸（DOPAC）水平的成比例更大的消耗，以及黑质中活化的小胶质细胞的更大增加。在12个月大时，甲基苯丙胺治疗的GDNF（+/）-小鼠表现出较低的运动活动和较低水平的酪氨酸羟化酶免疫反应性，多巴胺，DOPAC，和血清素比野生型小鼠。GDNF（+/）-小鼠纹状体多巴胺转运体活性的增加可能是其对甲基苯丙胺反应差异的基础。这些数据表明，在年轻人中使用甲基苯丙胺，当与整个生命中较低水平的GDNF相结合时，可能会在衰老过程中沉淀帕金森样行为的出现。
Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 x 10 mg/kg, i. p., at 2 h intervals), GDNF(+/)-mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF(+/)-mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF(+/)-mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging.