【摘要】：背景 阿片成癮是一種慢性復發(fā)性腦病,可導致一系列嚴重的社會和經濟問題。長期應用可產生精神依賴和軀體依賴,一旦停藥將產生戒斷綜合癥。戒斷癥狀令物質成癮者極其厭惡,從而負性強化了沖動的覓藥行為和復吸。本文以慢性嗎啡依賴大鼠納洛酮催癮戒斷建立的CPA動物模型為載體,研究成癮戒斷后的神經機制。 目的 分析慢性嗎啡依賴納洛酮催癮戒斷大鼠條件性位置厭惡(conditioned place aversion, CPA)建立前后、消退后及重建后,與成癮密切相關的腦區(qū)伏隔核殼區(qū)(the shell of nucleus accumbens, AcbSH)、杏仁核中央核(central amygdaloid nuclei, CeA)及腹側被蓋區(qū)(ventral tegmental area, VTA)內蛋白激酶A (protein kinase A, PKA)和Kappa阿片受體(Kappa opioid receptor, KOR)表達的適應性變化,探討嗎啡成癮戒斷后厭惡動機形成的生物學基礎。 方法 1.將雄性Sprague-Dawley (SD)大鼠72只隨機分為研究組,即慢性嗎啡注射+納洛酮催癮組morphine+naloxone, MN);對照組,即慢性嗎啡注射+生理鹽水催癮組(morphine+saline, MS);慢性生理鹽水注射+納洛酮催癮組(saline+naloxone,SN),每組24只。慢性嗎啡注射(10mg/kg,BID,IP)連續(xù)6.5天,在第七天下午(14：00)后給予一次納洛酮(0.3mg/kg,IP)催癮,同時與條件性位置訓練箱搭配建立CPA模型。 2.采用免疫組織化學方法分別在CPA建立前后、消退后及重建后觀察AcbSH、 CeA和VTA內PKA和Kappa阿片受體蛋白表達情況。 結果 1.CPA建立前,研究組(MN組)和對照組(MS組和SN組)PKA和Kappa阿片受體蛋白表達水平在AcbSH、CeA和VTA內差異均無顯著性。CPA建立后,研究組(MN組)和對照組(MS組和SN組)之間PKA蛋白表達水平在AcbSH(F=36.516,P=0.000)和VTA(F=9.853,P=0.018)內差異具有顯著性。其中在AcbSH內,MN組(109.50±4.661)高于MS組(126.50±3.697；P0.001)和SN組(133.50±6.364；P0.001)。在VTA內,MN組(127.50±3.536)高于MS組(140.50±3.697；P0.05)和SN組(138±2.944；P0.05)。Kappa阿片受體蛋白表達在CeA內差異具有顯著性(F=27.833,P=0.000),MN組(99.56±7.667)高于SN組(118.25±1.708；P0.001),低于MS組(85.43±7.807；P0.05)。 消退后,在各被檢腦區(qū)PKA和Kappa阿片受體蛋白表達差異均無顯著性。重建后,三組PKA蛋白表達水平在AcbSH (F=5.039,P=0.014)和VTA (F=11.261,P=0.018)內差異均有顯著性。其中在AcbSH內,MN組(118.18±10.058)低于MS組(126.50±3.697；P0.01),高于SN組(133.50±6.364；P0.05)。在VTA內,MN組(117.33±3.053)高于MS組(146.00±11.533；P0.01)和SN組(141.00±2.243；P0.05)。而Kappa阿片受體蛋白在各被檢腦區(qū)表達差異均無顯著性。 2.MN組在CPA建立前后、消退后及重建后,縱向比較PKA和Kappa阿片受體蛋白表達均出現(xiàn)不同程度的適應性變化：PKA在AcbSH (F=5.321,P=0.004)和CeA (F=7.256,P=0.029)各個時間點比較差異有顯著性,同樣Kappa阿片受體在AcbSH (F=3.820,P=0.016), CeA (F=3.153,P=0.039)和VTA(F=10.216,P=0.004)的差異也具有顯著性。而MS組和SN組在CPA的各個時間點,PKA和Kappa阿片受體蛋白表達差異均無顯著性。 結論 1.AcbSH、CeA和VTA內PKA和Kappa阿片受體存在適應性變化,這種變化可能是物質依賴戒斷后相關腦區(qū)神經可塑性變化的重要分子學基礎。 2.AcbSH、CeA和VTA內AC-cAMP-PKA-CREB通路上調,可能是CPA建立的神經機制。
[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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