利他林改善前额叶皮层工作记忆的机制研究

发布时间：2018-01-14 14:27

本文关键词：利他林改善前额叶皮层工作记忆的机制研究　出处：《复旦大学》2014年博士论文　论文类型：学位论文

【摘要】：利他林(Methylphenidate, MPH)是临床治疗注意力缺损多动症(Attention Deficit Hyperactivity Disorder, ADHD)的常用药物。临床和动物实验研究表明,利他林可以显著改善ADHD患者的认知功能,并且对正常人和动物也有相似的改善效应。利他林是单胺转运体抑制剂,通过抑制单胺类递质的再摄取,提高其在突触间隙的浓度从而达到治疗效果,这是目前普遍认可的利他林的疗效机制。然而,利他林改善认知功能的细胞机制尚不清楚。本工作采用行为药理学和蛋白免疫印迹技术,研究了利他林改善大鼠工作记忆的细胞机制。1.大鼠工作记忆能力与内侧前额叶皮层(mPFC) NMDAR和AMPAR膜表达量相关。皮下注射利他林显著改善大鼠工作记忆,同时伴随mPFC脑区NMDAR和AMPAR膜表达上调。2.利他林对工作记忆的改善效应需要mPFC脑区NMDAR膜表达量升高。阻断mPFC脑区NMDAR膜表达上调,利他林改善工作记忆的效应不再出现；药理学手段上调mPFC脑区NMDAR膜表达,可模拟利他林的改善效应。3.利他林对工作记忆的改善效应需要mPFC脑区NR2B亚基的介导,但不需要GluR1亚基。mPFC局部注射NR2B拮抗剂,利他林对工作记忆的改善效应不再存在；GluR1拮抗剂则无此效应。4.利他林通过多巴胺D1受体的激活上调mPFC脑区NMDAR膜表达,从而改善工作记忆。阻断D1受体,可抑制利他林引起的mPFC脑区NMDAR膜表达上调,抑制利他林对工作记忆的改善效应。以上结果表明,利他林通过增加mPFC脑区NMDAR膜表达量来改善工作记忆,这一过程依赖D1受体的激活。
[Abstract]:Ritalin (Methylphenidate, MPH) is a clinical treatment of attention deficit hyperactivity disorder (Attention Deficit Hyperactivity Disorder, ADHD) of the commonly used drugs. Clinical studies and animal experiments show that Ritalin can significantly improve cognitive function in patients with ADHD, and also improve the effect similar to normal human and animal. Ritalin is a monoamine transporter inhibitor. By inhibiting reuptake of monoamine neurotransmitters, increasing its concentration in the synaptic space so as to achieve the therapeutic effect, which is the effective mechanism of Ritalin is generally accepted. However, Ritalin improved cellular mechanisms of cognitive function is not clear. The behavioral pharmacology and Western blotting studies, Ritalin improves working memory rats working memory ability of rats and the mechanism of.1. cells in the medial prefrontal cortex (mPFC) and NMDAR AMPAR expression. The membrane under the skin injection of altruism Lin significantly improved working memory in rats, accompanied by mPFC brain NMDAR and AMPAR membrane expression improvement effect of Ritalin on the upregulation of.2. working memory to mPFC brain NMDAR membrane expression increased. Blocking mPFC brain NMDAR membrane expression, the effect of Ritalin improves working memory no longer appear; expression means of pharmacology NMDAR upregulation of mPFC brain in film, which can simulate the improvement effect of Ritalin to improve.3. effect of Ritalin on working memory to NR2B mPFC brain subunit mediated, but do not require the GluR1 subunit of.MPFC local injection of NR2B antagonist, improve the effect of Ritalin on working memory no longer exists; the activation of the GluR1 antagonist.4. had no such effect of altruism the forest through the dopamine D1 receptor upregulation of NMDAR mPFC expression of brain membrane, thereby improving working memory. The blocking of the D1 receptors, NMDAR expression of mPFC cortex membrane can inhibit Ritalin caused by the inhibition of Ritalin on the work record The results suggest that alalin improves working memory by increasing the expression of NMDAR membrane in the mPFC brain region, which depends on the activation of the D1 receptor.

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R96

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