Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum
Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum
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DOI：
10.1016/j.neuroscience.2006.10.035
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发表时间：
2007-02-09
期刊：
影响因子：
3.3
通讯作者：
Wilkinson, M.
中科院分区：
文献类型：
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作者：
Chase, T.;Carrey, N.;Wilkinson, M.
哌醋甲酯(MPH)是一种用于治疗儿童注意缺陷多动障碍的精神刺激药物。为了探讨慢性MPH的中枢效应，我们研究了反复MPH后幼鼠和成年大鼠脑内即刻早期效应基因、活性调节细胞骨架相关蛋白(ARC)和神经营养因子、脑源性神经营养因子(BDNF)的表达。青春期前(出生后25-38天)和成年(PD 53-66天)雄性大鼠每天注射一次生理盐水或MPH(2或10 mg/kg；S.C.)14天。或b)注射生理盐水13天，然后单次注射MPH(2或10 mg/kg；S.C.)。为了确定mph可能的长期影响，青春期前的大鼠在14天的治疗后被允许4周的无药期，然后给予挑战剂量的mph。我们首次证明，急性注射MPH可增加青春期前大鼠纹状体和扣带/额叶皮质中活性调节细胞骨架蛋白(ARC)和ARCmRNA的水平。这种反应被慢性MPH显著减弱。在青春期前的大鼠中观察到的ARC表达的脱敏在成年纹状体中持续存在，在后来的MPH攻击之后。与这些数据相比，我们观察到mph对BDNF表达的影响很小。我们还开发了一种有效的、无应激的技术来治疗口服MPH的自由活动的未成熟大鼠。与上述结果一致，我们观察到口服MPH(7.5和10 mg/kg)也增加了青春期前大鼠纹状体中ARC的表达。然而，与注射MPH不同的是，重复口服MPH(7.5 mg/kg)并不改变正常的ARC反应。这一结果提出了一种重要的可能性，即口服剂量的mph复制了临床上相关的mph水平，可能不会下调基因表达，至少在短期内(14天)是这样。我们使用质谱仪证实，在我们的实验中使用的口服MPH剂量的血液水平在儿童观察到的临床范围内。因此，我们描述的新的口服给药范式为进一步探索慢性药物暴露对发育中的大鼠大脑中枢基因表达的影响提供了一个具有临床意义的动物模型。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Methylphenidate (MPH) is a psychostimulant drug used to treat attention deficit hyperactivity disorder in children. To explore the central effects of chronic MPH, we investigated the expression of an effector immediate early gene, activity regulated cytoskeletal associated (arc), and the neurotrophin, brain-derived neurotrophic factor (bdnf) in the brain of immature and adult rats following repeated MPH. Prepubertal (postnatal day (PD) 25-38) and adult (PD 53-66) male rats were injected once daily for: a) 14 days with saline or MPH (2 or 10 mg/kg; s.c.) or b) 13 days with saline followed by a single dose of MPH (2 or 10 mg/kg; s.c.). To determine possible long-term effects of MPH, prepubertal rats were allowed a drug-free period of 4 weeks following the 14 days of treatment, and then were given a challenge dose of MPH. We demonstrated, for the first time, that an acute injection of MPH increased levels of activity-regulated cytoskeletal protein (ARC) and arc mRNA in the prepubertal rat striatum and cingulate/frontal cortex. This response was significantly attenuated by chronic MPH. The desensitization in arc expression observed in prepubertal rats persisted in the adult striatum following a later MPH challenge. In contrast to these data we observed little effect of MPH on bdnf expression. We also developed an effective, non-stressful technique to treat freely moving immature rats with oral MPH. Consistent with the results described above, we observed that oral MPH (7.5 and 10 mg/kg) also increased arc expression in the prepubertal rat striatum. However, unlike the effects of injected MPH, repeated oral MPH (7.5 mg/kg) did not alter the normal arc response. This result raises the important possibility that oral doses of MPH that reproduce clinically relevant blood levels of MPH may not down-regulate gene expression, at least in the short term (14 days). We confirmed, using mass spectrometry, that the oral doses of MPH used in our experiments yielded blood levels within the clinical range observed in children. The novel oral administration paradigm that we describe thus provides a clinically relevant animal model to further explore the effects of chronic drug exposure on central gene expression in the developing rat brain. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.