慢性吗啡依赖大鼠条件性位置厌恶模型部分脑区蛋白激酶A和Kappa阿片受体表达变化

发布时间：2019-06-15 19:09

【摘要】：背景 阿片成瘾是一种慢性复发性脑病,可导致一系列严重的社会和经济问题。长期应用可产生精神依赖和躯体依赖,一旦停药将产生戒断综合症。戒断症状令物质成瘾者极其厌恶,从而负性强化了冲动的觅药行为和复吸。本文以慢性吗啡依赖大鼠纳洛酮催瘾戒断建立的CPA动物模型为载体,研究成瘾戒断后的神经机制。 目的 分析慢性吗啡依赖纳洛酮催瘾戒断大鼠条件性位置厌恶(conditioned place aversion, CPA)建立前后、消退后及重建后,与成瘾密切相关的脑区伏隔核壳区(the shell of nucleus accumbens, AcbSH)、杏仁核中央核(central amygdaloid nuclei, CeA)及腹侧被盖区(ventral tegmental area, VTA)内蛋白激酶A (protein kinase A, PKA)和Kappa阿片受体(Kappa opioid receptor, KOR)表达的适应性变化,探讨吗啡成瘾戒断后厌恶动机形成的生物学基础。 方法 1.将雄性Sprague-Dawley (SD)大鼠72只随机分为研究组,即慢性吗啡注射+纳洛酮催瘾组morphine+naloxone, MN);对照组,即慢性吗啡注射+生理盐水催瘾组(morphine+saline, MS);慢性生理盐水注射+纳洛酮催瘾组(saline+naloxone,SN),每组24只。慢性吗啡注射(10mg/kg,BID,IP)连续6.5天,在第七天下午(14：00)后给予一次纳洛酮(0.3mg/kg,IP)催瘾,同时与条件性位置训练箱搭配建立CPA模型。 2.采用免疫组织化学方法分别在CPA建立前后、消退后及重建后观察AcbSH、 CeA和VTA内PKA和Kappa阿片受体蛋白表达情况。 结果 1.CPA建立前,研究组(MN组)和对照组(MS组和SN组)PKA和Kappa阿片受体蛋白表达水平在AcbSH、CeA和VTA内差异均无显著性。CPA建立后,研究组(MN组)和对照组(MS组和SN组)之间PKA蛋白表达水平在AcbSH(F=36.516,P=0.000)和VTA(F=9.853,P=0.018)内差异具有显著性。其中在AcbSH内,MN组(109.50±4.661)高于MS组(126.50±3.697；P0.001)和SN组(133.50±6.364；P0.001)。在VTA内,MN组(127.50±3.536)高于MS组(140.50±3.697；P0.05)和SN组(138±2.944；P0.05)。Kappa阿片受体蛋白表达在CeA内差异具有显著性(F=27.833,P=0.000),MN组(99.56±7.667)高于SN组(118.25±1.708；P0.001),低于MS组(85.43±7.807；P0.05)。 消退后,在各被检脑区PKA和Kappa阿片受体蛋白表达差异均无显著性。重建后,三组PKA蛋白表达水平在AcbSH (F=5.039,P=0.014)和VTA (F=11.261,P=0.018)内差异均有显著性。其中在AcbSH内,MN组(118.18±10.058)低于MS组(126.50±3.697；P0.01),高于SN组(133.50±6.364；P0.05)。在VTA内,MN组(117.33±3.053)高于MS组(146.00±11.533；P0.01)和SN组(141.00±2.243；P0.05)。而Kappa阿片受体蛋白在各被检脑区表达差异均无显著性。 2.MN组在CPA建立前后、消退后及重建后,纵向比较PKA和Kappa阿片受体蛋白表达均出现不同程度的适应性变化：PKA在AcbSH (F=5.321,P=0.004)和CeA (F=7.256,P=0.029)各个时间点比较差异有显著性,同样Kappa阿片受体在AcbSH (F=3.820,P=0.016), CeA (F=3.153,P=0.039)和VTA(F=10.216,P=0.004)的差异也具有显著性。而MS组和SN组在CPA的各个时间点,PKA和Kappa阿片受体蛋白表达差异均无显著性。 结论 1.AcbSH、CeA和VTA内PKA和Kappa阿片受体存在适应性变化,这种变化可能是物质依赖戒断后相关脑区神经可塑性变化的重要分子学基础。 2.AcbSH、CeA和VTA内AC-cAMP-PKA-CREB通路上调,可能是CPA建立的神经机制。
[Abstract]:background Opioid addiction is a chronic recurrent encephalopathy that can lead to a series of serious social and economic questions The long-term application can generate mental and physical dependence, and once the drug withdrawal will result in withdrawal synthesis The symptoms of the withdrawal cause the substance addicts to be extremely disgusted, so that the negative potentiation of the impulsiveness and the complex In this paper, a CPA animal model based on the withdrawal of naloxone in rats with chronic morphine dependence is used as a carrier to study the nerve machine after drug addiction withdrawal. System. Objective To analyze the conditional position aversion (CPA) of the rats with chronic morphine dependence on the dependence of naloxone on the conditional position aversion (CPA). The shell of nucleus accumbens (AcbSH) and the central amygdaloid n of the amygdala are closely related to the addiction. The changes of the expression of protein kinase A (PKA) and Kappa-opioid receptor (KOR) in the ventral tegmental area (VTA) and the expression of Kappa-opiate receptor (KOR) in the ventral tegmental area (VTA) were investigated. biological Basis of study. Method 1. The male Sprague-Dawley (SD) rats were randomly divided into the study group (i.e., the chronic morphine injection + naloxone group morpheine + naloxone, MN); the control group, that is, the chronic morphine injection and the normal saline group (morpheine + saline, MS); the chronic physiological saline injection and the naloxone hypnotics group (saline + nal oxone, SN)24. Chronic morphine injection (10 mg/ kg, BID, IP) for 6.5 days, and once naloxone (0.3 mg/ kg, IP) on the seventh day (14:00), while in conjunction with the conditioned position training box The method of immunohistochemistry was used to observe the PKA and Kapp in AcbSH, CeA and VTA after and after the establishment of CPA. a闃，

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