本文關(guān)鍵詞：酒精對大鼠腦組織內(nèi)神經(jīng)甾體的調(diào)節(jié)機(jī)制研究　出處：《河北醫(yī)科大學(xué)》2005年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 酒精 依賴 戒斷 神經(jīng)甾體 神經(jīng)甾體合成代謝酶 液相色譜-質(zhì)譜 免疫組織化學(xué)

【摘要】：神經(jīng)甾體特指大腦神經(jīng)元和膠質(zhì)細(xì)胞合成的甾體,可通過非基因機(jī)制作用于中樞GABAA、NMDA 等受體系統(tǒng),發(fā)揮其生理學(xué)效應(yīng),如鎮(zhèn)靜催眠、抗焦慮、抗驚厥等。一方面,神經(jīng)甾體可以抑制小鼠嗎啡依賴和耐受的形成,影響大鼠條件性位置偏愛的建立,發(fā)揮偏愛或嫌惡作用;還可影響大鼠的飲酒行為,顯著降低酒精依賴大鼠攝酒量,增加非酒精依賴大鼠的攝酒量,并能夠替代酒精的特定行為效應(yīng)。另一方面,酒精依賴、戒斷可誘發(fā)皮質(zhì)、海馬、小腦及血液中部分神經(jīng)甾體水平變化,改變GABAA受體的功能特性及其對神經(jīng)甾體的敏感性,使GABAA受體產(chǎn)生適應(yīng)性,此適應(yīng)性變化構(gòu)成了酒精依賴的神經(jīng)生物學(xué)基礎(chǔ),其分子機(jī)制可能涉及酒精誘導(dǎo)的細(xì)胞表面受體表達(dá)、亞細(xì)胞定位、突觸定位,受體磷酸化,神經(jīng)甾體水平和GABAA 受體亞基組成等改變。由此推測,酒精依賴可能與大腦特別是獎(jiǎng)賞回路各相關(guān)核團(tuán)的內(nèi)源性神經(jīng)甾體生物合成有關(guān),內(nèi)源性神經(jīng)甾體在酒精依賴與GABAA 受體的相互作用方面發(fā)揮著重要作用。 有關(guān)神經(jīng)甾體在中樞神經(jīng)系統(tǒng)中的正常合成與代謝途徑已基本闡明。研究表明急性酒精注射可以調(diào)節(jié)大鼠腦區(qū)內(nèi)神經(jīng)甾體合成代謝酶甾體快速調(diào)節(jié)蛋白(StAR)、3β-羥基甾體還原酶(3β-HSD)和3α-羥基甾體還原酶(3α-HSD) 的mRNA 表達(dá);慢性酒精處理可抑制WSP 鼠皮質(zhì)、海馬和杏仁核部位的5α-還原酶活性。慢性酒精處理是否影響伏隔核、杏仁核、腹側(cè)被蓋區(qū)、紋狀體和下丘腦等腦區(qū)其它神經(jīng)甾體合成代謝酶的表達(dá)活性未見文獻(xiàn)報(bào)道。慢性酒精依賴和戒斷影響大鼠部分腦區(qū)神經(jīng)甾體的水平,這種變化是否與神經(jīng)甾體合成代謝酶在中樞神經(jīng)系統(tǒng)中的表達(dá)調(diào)控相關(guān)尚待證實(shí)。 本實(shí)驗(yàn)采用固相萃取結(jié)合液相色譜-質(zhì)譜聯(lián)用技術(shù),建立了一種靈敏、準(zhǔn)確和特異性強(qiáng)的檢測方法,可以滿足大鼠腦組織及血漿中微量游離型或硫酸酯型神經(jīng)甾體的測定需要;采用大鼠酒精依賴和戒斷模型,研究大鼠酒精依賴和戒斷時(shí)不同腦區(qū)神經(jīng)甾體水平的變化;應(yīng)用免疫組織化學(xué)方法,研究膽固醇側(cè)鏈裂解酶(P450scc)蛋白和GABA_A α1 亞基
[Abstract]:Neurosteroids, specifically the steroids synthesized by neurons and glial cells in the brain, can exert physiological effects, such as sedation and hypnosis, by acting on the central GABA AANMDA receptor system through non-gene mechanisms. On the one hand, neurosteroids can inhibit the formation of morphine dependence and tolerance in mice, affect the establishment of conditioned place preference in rats, play a role of preference or aversion; It can also affect the drinking behavior of rats, significantly reduce the alcohol intake of alcohol dependent rats, increase the alcohol intake of non-alcohol dependent rats, and can replace the specific behavioral effects of alcohol. On the other hand, alcohol dependence. Withdrawal can induce changes in some neurosteroids in cortex, hippocampus, cerebellum and blood, change the functional characteristics of GABAA receptor and its sensitivity to neurosteroids, and make GABAA receptor adaptive. This adaptive change constitutes the neurobiological basis of alcohol dependence and its molecular mechanism may involve the expression of receptors subcellular localization synaptic localization and receptor phosphorylation induced by alcohol. The changes of neurosteroid level and GABAA receptor subunit composition suggest that alcohol dependence may be related to endogenous neurosteroid biosynthesis in the brain, especially in the relevant nuclei of the reward circuit. Endogenous neurosteroids play an important role in alcohol-dependent interactions with GABAA receptors. The normal biosynthesis and metabolic pathway of neurosteroids in the central nervous system (CNS) have been elucidated. Star. MRNA expression of 3 尾 -hydroxysteroid reductase 3 尾 -HSDand 3 偽 -hydroxysteroid reductase 3 偽 -HSDs; Chronic alcohol treatment could inhibit the activity of 5 偽 -reductase in cortex, hippocampus and amygdala of WSP rats. Whether chronic alcohol treatment affected nucleus accumbens, amygdala, ventral tegmental area. The expression activity of other neurosteroid synthase in striatum and hypothalamus has not been reported. Chronic alcohol dependence and withdrawal affect the level of neurosteroids in some brain regions of rats. Whether this change is related to the expression and regulation of neurosteroid synthase in the central nervous system remains to be confirmed. A sensitive, accurate and specific detection method was established by solid phase extraction (SPE) combined with liquid chromatography-mass spectrometry (LC-MS). It can meet the needs of the determination of free or sulfate type neurosteroids in brain tissue and plasma of rats. The changes of neurosteroid levels in different brain regions of rats with alcohol dependence and withdrawal were studied by using the model of alcohol dependence and withdrawal in rats. Study on the protein and GABA_A 偽 1 subunit of cholesterol side chain cleavage enzyme P450 SCC by immunohistochemical method
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2005
【分類號】：R363

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本文編號：1425569