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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum.
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Methylphenidate regulates activity regulated cytoskeletal associated but not brain-derived neurotrophic factor gene expression in the developing rat striatum.

机译：哌醋甲酯可调节发育中的大鼠纹状体中活性调节的细胞骨架相关但非脑源性神经营养因子基因的表达。

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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.
机译：哌醋甲酯（MPH）是一种精神刺激药，用于治疗儿童的注意力缺陷多动障碍。为了探索慢性MPH的中心作用，我们研究了未成熟和成年大鼠大脑中的效应子立即早期基因，活性调节的细胞骨架相关（arc）以及神经营养蛋白，脑源性神经营养因子（bdnf）的表达。 MPH。每天一次给青春期前（出生后（PD）25-38天）和成年（PD 53-66）成年雄性大鼠注射：a）14天的生理盐水或MPH（2或10 mg / kg; sc）或b）13天盐水，然后单剂量的MPH（2或10 mg / kg; sc）。为了确定MPH的长期作用，在治疗14天后，将青春期前的大鼠禁药4周，然后给予MPH激发剂量。我们首次证明，急性注射MPH可增加青春期前纹状体和扣带/额叶皮层中活性调节的细胞骨架蛋白（ARC）和arc mRNA的水平。慢性MPH可明显缓解这种反应。在随后的MPH攻击后，在青春期前大鼠中观察到的弧表达的脱敏作用持续存在于成年纹状体中。与这些数据相反，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，无压力的技术来治疗经口MPH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的弧表达。但是，与注射MPH的效果不同，反复口服MPH（7.5 mg / kg）不会改变正常的电弧反应。该结果提出了重要的可能性，即至少在短期内（14天），可重现临床相关血液中MPH含量的MPH口服剂量可能不会下调基因表达。我们使用质谱法证实，在我们的实验中口服MPH所产生的血液水平处于儿童所观察到的临床范围内。因此，我们描述的新型口服给药范例提供了一种临床上相关的动物模型，以进一步探索慢性药物暴露对发育中大鼠大脑中中心基因表达的影响。

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