Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum
Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum
复制标题
DOI：
10.1046/j.1460-9568.2003.02892.x
复制
发表时间：
2003-09-01
影响因子：
3.4
通讯作者：
Steiner, H
中科院分区：
文献类型：
--
作者：
Brandon, CL;Steiner, H
哌醋甲酯是一种精神兴奋剂，可抑制多巴胺转运蛋白并在纹状体中产生多巴胺溢出，类似于可卡因的作用。过度的多巴胺作用通常与多巴胺感受神经元基因表达的变化有关。关于哌醋甲酯对基因调控的影响知之甚少。我们研究了已知会产生行为改变的哌醋甲酯治疗方案是否会改变纹状体中的基因表达。使用原位杂交组织化学，我们评估了急性和重复哌甲酯治疗对青春期大鼠即早期基因（c-fos、zif268）和神经肽（强啡肽、P物质、脑啡肽）表达的影响。急性哌醋甲酯治疗（0-10 mg/kg，腹腔注射）使 c-fos 和 zif268 的表达出现剂量依赖性增加。这些效应在背侧纹状体中至尾侧纹状体水平最为明显，并且在剂量低至 2 mg/kg 时即可发现。哌醋甲酯重复治疗（10 mg/kg/天，7 天）增加了强啡肽的表达，这与不同纹状体区域的急性即早期基因反应高度相关。此外，重复哌醋甲酯治疗后，可卡因诱导的 c-fos 和 zif268 以及 P 物质的表达在整个纹状体中显着减弱。重复哌醋甲酯治疗的这些效果与可卡因或其他精神兴奋剂重复治疗产生的效果相似，并且被认为反映了药物诱导的神经适应。因此，我们的研究结果表明，急性和重复的哌醋甲酯治疗可以产生与其他精神兴奋剂类似的分子改变。
Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants.