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利他林对幼年大鼠额叶皮层小清蛋白阳性中间神经元c-Fos表达的影响

张迎春, 朱学清, 张雪寒

复旦大学脑科学研究院，上海 200032

摘要

目前已知注意力缺损多动症(attention-deficit hyperactivity disorder, ADHD)的发病机制与额叶皮层活动降低、多巴胺(dopamine, DA)和去甲肾上腺素(norepinephrine, NE)不足有关。利他林目前是临床治疗ADHD的首选使用药物。它是单胺类递质转运体抑制剂，通过阻断转运体，提高细胞外DA和NE浓度，达到治疗效果。除此之外，利他林还可以增强皮层锥体神经元的兴奋性，增强皮层整体的活动。但是，利他林对中间神经元活动的影响尚不清楚。本研究采用药理学和免疫组织化学技术，探讨全身注射利他林对幼年大鼠眶额皮层(orbitofrontal cortex, OFC)、前额叶皮层(prefrontal cortex, PFC)和前扣带皮层(anterior cingulate cortex, ACC)中小清蛋白(parvalbumin, PV)阳性中间神经元c-Fos表达的影响。结果显示，利他林显著增加OFC的内侧区(MO)、腹侧区(VO)和外侧区(LO) c-Fos的表达，但是仅增加MO区和VO区PV阳性中间神经元c-Fos的表达，对LO区PV阳性中间神经元c-Fos表达没有影响；对PFC前边缘区(PrL)和缘下回区(IL)的分析显示，只有剂量为1 mg/kg的利他林可使这两个区域c-Fos的表达和PV阳性中间神经元c-Fos的表达明显增多，而8 mg/kg的利他林则无显著作用。利他林可使ACC中c-Fos的表达和PV阳性中间神经元c-Fos的表达显著增多。以上结果表明，对幼年大鼠全身给予利他林，可以激活其额叶皮层PV阳性中间神经元，提示利他林可能通过激活皮层PV阳性神经元调控皮层锥体神经元动作电位的发放和神经元网络的同步活动，影响皮层的输出。

关键词： 利他林; 小清蛋白中间神经元 ; c-Fos ; 幼年大鼠

分类号：Q42

Effect of methylphenidate on c-Fos expression in parvalbumin interneurons of juvenile rat frontal cortex

ZHANG Ying-Chun, ZHU Xue-Qing, ZHANG Xue-Han

Institutes of Brain Science, Fudan University, Shanghai 200032, China

Abstract

The etiology of attention-deficit hyperactivity disorder (ADHD) has been generally linked to the decrease in cortex activity, as well as to the reduction in dopamine (DA) and norepinephrine (NE) levels. Methylphenidate (MPH; Ritalin) is the most commonly prescribed medication for ADHD. It has been determined that MPH acts primarily on the dopaminergic and noradrenergic systems through blockade of DA and NE transporters, thereby increasing the concentrations of these neurotransmitters in the brain to correct the attention deficits and hyperactivity. In addition, MPH has been proposed to increase the excitability of pyramidal neurons and the overall activity of cortex. However, the effect of MPH on the activity of interneurons is lack of investigation. Here, by using immunohistochemistry technique, we examined c-Fos expression in parvalbumin (PV)-expressing interneurons of frontal cortex of rats (28-day-old) at 1 h after a single MPH infusion (1 or 8 mg/kg; s.c.). We analyzed the c-Fos expression in the medial orbitofrontal cortex (MO), ventral orbitofrontal cortex (VO), and lateral orbitofrontal cortex (LO) subregions of orbitofrontal cortex (OFC), as well as the prelimbic cortex (PrL) and infralimbic cortex (IL) subregions of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) after MPH infusion. Our data showed that MPH increased c-Fos expression in MO, VO and LO, and the c-Fos expression in PV-expressing interneurons elevated significantly in MO, VO, but not in LO. Meanwhile, the increases of c-Fos expression in PrL and IL, as well as in PV-expressing interneurons of these two regions, were only induced by 1 mg/kg MPH, but not 8 mg/kg. Both 1 and 8 mg/kg MPH dramatically increased c-Fos expression in ACC, especially, in PV-expressing interneurons of ACC as well. In conclusion, acute systemic injection of MPH significantly increases the c-Fos expression in PV-expressing interneurons of the OFC, PFC and ACC.

Key words: methylphenidate; parvalbumin interneuron ; c-Fos ; juvenile rat

收稿日期：2017-05-15　　录用日期：2017-07-19

通讯作者：张雪寒　　E-mail: xuehanzhang@fudan.edu.cn

引用本文：

张迎春, 朱学清, 张雪寒. 利他林对幼年大鼠额叶皮层小清蛋白阳性中间神经元c-Fos表达的影响[J]. 生理学报 2017; 69 (4): 378-384.

ZHANG Ying-Chun, ZHU Xue-Qing, ZHANG Xue-Han. Effect of methylphenidate on c-Fos expression in parvalbumin interneurons of juvenile rat frontal cortex. Acta Physiol Sin 2017; 69 (4): 378-384