Yano M, Steiner H
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, IL 60064, USA.
Neuroscience. 2005;132(3):855-65. doi: 10.1016/j.neuroscience.2004.12.019.
Corticostriatal circuits participate in limbic, attentional, motor and other networks, and are implicated in psychostimulant addiction. The psychostimulant methylphenidate is used in the treatment of attention-deficit hyperactivity disorder and for recreational purposes. Recent studies indicate that methylphenidate alters gene expression in striatal neurons. We investigated whether methylphenidate affects gene regulation in specific corticostriatal circuits, by comparing drug-induced molecular changes in different functional domains of the striatum with changes in their cortical input regions. In order to assess the potential functional significance of methylphenidate-induced molecular changes, we examined members of two different classes of plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a. Acute methylphenidate administration in adult rats increased the expression of Homer 1a and zif 268 in both cortex and striatum in a dose-dependent and regionally selective manner. These changes in gene expression occurred after doses of 2 mg/kg (i.p.) and higher, and were highly correlated between cortical regions and their striatal targets. In the cortex, increases were maximal in the medial agranular (premotor) and cingulate cortex, followed by motor and somatosensory cortex, and were minimal in the insular cortex. Correspondingly, in the striatum, increases were most robust in sensorimotor sectors that receive medial agranular input, and were weaker or absent in ventral sectors. The methylphenidate-induced increases in cortical Homer 1a and zif 268 expression were also correlated with increases in striatal substance P and dynorphin expression (direct pathway). Overall, the regional distribution of methylphenidate-induced molecular changes in the striatum was similar to that of changes induced by psychostimulants such as cocaine. These findings demonstrate that methylphenidate affects transcription and synaptic plasticity regulatory proteins in specific corticostriatal circuits, including those implicated in attentional functions and psychostimulant addiction. Such methylphenidate-induced gene regulation may contribute to the therapeutic effects and/or abuse liability of this psychostimulant.
皮质纹状体回路参与边缘系统、注意力、运动及其他网络，且与精神兴奋剂成瘾有关。精神兴奋剂哌甲酯用于治疗注意力缺陷多动障碍及非医疗目的使用。最近的研究表明，哌甲酯会改变纹状体神经元中的基因表达。我们通过比较药物诱导的纹状体不同功能区域的分子变化及其皮质输入区域的变化，来研究哌甲酯是否会影响特定皮质纹状体回路中的基因调控。为了评估哌甲酯诱导的分子变化的潜在功能意义，我们检测了两类不同的可塑性相关分子，即转录因子zif 268和突触可塑性因子Homer 1a。成年大鼠急性给予哌甲酯后，皮质和纹状体中Homer 1a和zif 268的表达均呈剂量依赖性和区域选择性增加。基因表达的这些变化在剂量为2mg/kg（腹腔注射）及更高时出现，且在皮质区域与其纹状体靶点之间高度相关。在皮质中，内侧无颗粒（运动前）和扣带回皮质的增加最为显著，其次是运动和体感皮质，而岛叶皮质的增加最小。相应地，在纹状体中，接受内侧无颗粒输入的感觉运动区增加最为明显，而腹侧区则较弱或无增加。哌甲酯诱导的皮质Homer 1a和zif 268表达增加也与纹状体P物质和强啡肽表达增加（直接通路）相关。总体而言，哌甲酯诱导的纹状体分子变化的区域分布与可卡因等精神兴奋剂诱导的变化相似。这些发现表明，哌甲酯会影响特定皮质纹状体回路中的转录和突触可塑性调节蛋白，包括那些与注意力功能和精神兴奋剂成瘾有关的蛋白。这种哌甲酯诱导的基因调控可能有助于这种精神兴奋剂的治疗效果和/或滥用倾向。
