Differential regulation of psychostimulant-induced gene expression of brain derived neurotrophic factor and the immediate-early gene Arc in the juvenile and adult brain
Differential regulation of psychostimulant-induced gene expression of brain derived neurotrophic factor and the immediate-early gene Arc in the juvenile and adult brain
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DOI：
10.1111/j.1460-9568.2008.06601.x
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发表时间：
2009-02-01
影响因子：
3.4
通讯作者：
Zetterstroem, Tyra S. C.
中科院分区：
文献类型：
--
作者：
Banerjee, Partha S.;Aston, James;Zetterstroem, Tyra S. C.
精神兴奋剂药物被广泛用于儿童注意力缺陷/多动症的治疗。最近的动物研究表明，在生命早期暴露于这些物质可能对大脑发育有害。在这里，第一次，哌甲酯（MPH）和d-苯丙胺（AMPH）对神经元发育和可塑性，脑源性神经营养因子（BDNF）和效应立即早期基因活性调节，细胞内相关蛋白（Arc）的两个关键基因的表达的影响，在青少年和成年大鼠进行了检查。两种MPH [2 mg/kg，腹膜内（i. p.）]和AMPH（0.5mg/kg，i.p.）诱导青少年海马和皮质脑区bdnf mRNA显著降低，而成年人的影响明显较小（海马）或相反（额叶皮质）。相比之下，Arc mRNA减少（海马和顶叶皮质），在很大程度上不受影响（额叶皮质）或增加（纹状体）在青少年，而在成年人中，Arc mRNA增加在大多数大脑区域。MPH诱导的运动也进行了测量，并显示出一个小得多的增加在青少年比成年人。总之，我们的数据表明，MPH和AMPH对神经发育重要基因，bdnf和Arc的表达的影响，在青少年和成年大鼠中显着不同，与青少年表现出大脑区域特异性减少的证据在这两个基因。这些对基因表达的年龄依赖性影响可能与动物模型中报告的精神兴奋剂的长期有害影响有关。
Psychostimulant drugs are widely used in children for the treatment of attention-deficit/hyperactivity disorder. Recent animal studies have suggested that exposure to these agents in early life could be detrimental to brain development. Here, for the first time, the effect of methylphenidate (MPH) and d-amphetamine (AMPH) on the expression of two key genes for neuronal development and plasticity, brain-derived neurotrophic factor (bdnf) and the effector immediate early gene activity-regulated, cytoskeletal-associated protein (Arc), was examined in both juvenile and adult rats. Both MPH [2 mg/kg, intraperitoneal (i.p.)] and AMPH (0.5 mg/kg, i.p.) induced marked decreases of bdnf mRNA in hippocampal and cortical brain regions of juveniles, whereas effects in adults were significantly less (hippocampus) or opposite (frontal cortex). In comparison, Arc mRNA was decreased (hippocampus and parietal cortex), largely unaffected (frontal cortex) or increased (striatum) in juveniles, whereas in adults, Arc mRNA increased in most brain regions. MPH-induced locomotion was also measured, and showed a much smaller increase in juveniles than in adults. In summary, our data show that the effects of MPH and AMPH on expression of the neurodevelopmentally important genes, bdnf and Arc, differ markedly in juvenile and adult rats, with juveniles showing evidence of brain region-specific decreases in both genes. These age-dependent effects on gene expression may be linked with the reported long-term harmful effects of psychostimulants in animal models.