發(fā)布時(shí)間：2018-05-06 07:00

  本文選題：行為敏化 + γ-氨基丁酸��； 參考：《吉林大學(xué)》2012年博士論文

【摘要】：γ-氨基丁酸是中樞神經(jīng)系統(tǒng)中很重要的抑制性神經(jīng)遞質(zhì)，它是一種天然存在的氨基酸，具有極其重要的生理功能。γ-氨基丁酸作用于動(dòng)物細(xì)胞中的GABA受體，GABA受體是一個(gè)氯離子通道，GABA的抑制性或興奮性是依賴于細(xì)胞膜內(nèi)外的氯離子濃度，GABA受體被激活后，導(dǎo)致氯離子通道開放，能增加細(xì)胞膜對(duì)氯離子通透性，引起細(xì)胞膜超極化，抑制神經(jīng)細(xì)胞元活性。 研究發(fā)現(xiàn)γ-氨基丁酸能夠增強(qiáng)嗎啡鎮(zhèn)痛，對(duì)抗嗎啡耐受及軀體依賴。本文的主要目的是研究γ-氨基丁酸抗嗎啡精神依賴的作用及其可能機(jī)制。研究表明重復(fù)的給予嗎啡可以誘導(dǎo)行為敏化，雖然有研究報(bào)道γ-氨基丁酸系統(tǒng)參與了行為敏化，但其內(nèi)在機(jī)制卻有待進(jìn)一步探討。在本研究中我們探討了GABAB受體激動(dòng)劑在嗎啡誘導(dǎo)的行為敏化中的作用，并進(jìn)一步研究了其內(nèi)在機(jī)制。研究表明嗎啡連續(xù)給藥4天，經(jīng)過3天的停藥戒斷后，嗎啡單次注射3mg/kg，，明顯的誘導(dǎo)了大鼠行為敏化的形成；具體表現(xiàn)在大鼠的運(yùn)動(dòng)活性顯著增強(qiáng)，暗示了大鼠行為敏化模型的建立。γ-氨基丁酸的慢性處理和急性處理能明顯降低嗎啡誘導(dǎo)的行為敏化的形成和表達(dá)。其內(nèi)在機(jī)制可能是Baclofen激活γ-氨基丁酸受體，調(diào)節(jié)相關(guān)基因的表達(dá)有關(guān)。此外，我們通過腦微透析技術(shù)研究發(fā)現(xiàn)，嗎啡單劑量單次注射誘導(dǎo)行為敏化表達(dá)時(shí)，大鼠活動(dòng)性增強(qiáng)與伏隔核多巴胺釋放有密切關(guān)系，而Baclofen預(yù)處理能夠明顯減低伏隔核多巴胺的釋放。 同時(shí)，我們研究了大鼠行為敏化模型中不同腦區(qū)相關(guān)基因的表達(dá)情況，研究發(fā)現(xiàn)在伏隔核pCREB表達(dá)明顯降低，而ΔFosB表達(dá)明顯升高。Baclofen預(yù)處理明顯抑制了嗎啡引起的行為增強(qiáng)，并明顯減低了伏隔核ΔFosB表達(dá)。但對(duì)伏隔核pCREB表達(dá)降低，有一定的逆轉(zhuǎn)作用，但沒有明顯的統(tǒng)計(jì)學(xué)意義。 結(jié)論：本文在以往研究的基礎(chǔ)上，深入研究了γ-氨基丁酸B受體激動(dòng)劑Baclofen通過降低伏隔核多巴胺的釋放，抑制了嗎啡誘導(dǎo)的行為敏化，暗示了γ-氨基丁酸B受體激動(dòng)劑Baclofen潛在的抗嗎啡精神依賴作用。進(jìn)一步的研究發(fā)現(xiàn)Baclofen抑制嗎啡誘導(dǎo)的行為敏化與伏隔核ΔFosB和pCREB的表達(dá)密切相關(guān)。
[Abstract]:緯-aminobutyric acid is an important inhibitory neurotransmitter in the central nervous system. It is a natural amino acid. Gamma-aminobutyric acid acts on the GABA receptor in animal cells. The inhibitory or excitatory activity of GABA receptor is dependent on the concentration of chloride ions in and out of the cell membrane. The opening of chloride channel can increase the permeability of cell membrane to chloride ion, cause cell membrane hyperpolarization and inhibit the activity of neuronal cells. It was found that 緯-aminobutyric acid could enhance morphine analgesia and antagonize morphine tolerance and somatic dependence. The main purpose of this paper is to study the effect of 緯-aminobutyric acid on morphine dependence and its possible mechanism. Repeated administration of morphine can induce behavioral sensitization. Although it has been reported that 緯 -aminobutyric acid system is involved in behavioral sensitization, its intrinsic mechanism needs to be further explored. In this study, we investigated the role of GABAB receptor agonists in morphine induced behavioral sensitization and its underlying mechanisms. The results showed that after 4 days of continuous administration of morphine, a single injection of morphine at 3 mg / kg significantly induced the formation of behavioral sensitization in rats after 3 days of withdrawal, which was manifested in a marked increase in the motor activity of the rats. It suggested that the establishment of behavioral sensitization model in rats. Chronic and acute treatment of 緯 -aminobutyric acid could significantly reduce the formation and expression of behavioral sensitization induced by morphine. The underlying mechanism may be that Baclofen activates 緯-aminobutyric acid receptors and regulates the expression of related genes. In addition, we found that the increased activity of rat was closely related to dopamine release from nucleus accumbens when single dose of morphine was used to induce behavioral sensitization. Baclofen pretreatment significantly reduced the release of dopamine from nucleus accumbens. At the same time, we studied the expression of genes related to different brain regions in the behavioral sensitization model of rats. The results showed that the expression of pCREB in nucleus accumbens was significantly decreased, while the expression of 螖 FosB was significantly increased. Baclofen pretreatment significantly inhibited the behavioral enhancement induced by morphine. The expression of 螖 FosB in nucleus accumbens was significantly decreased. However, the expression of pCREB in nucleus accumbens was decreased and reversed to some extent, but there was no statistical significance. Conclusion: on the basis of previous studies, Baclofen, a gamma-aminobutyric acid B receptor agonist, inhibits the behavioral sensitization induced by morphine by reducing dopamine release in nucleus accumbens. It suggests that 緯-aminobutyric acid B receptor agonist Baclofen has a potential anti-morphine-dependent effect. Further studies showed that Baclofen inhibited morphine induced behavioral sensitization and was closely related to the expression of 螖 FosB and pCREB in nucleus accumbens.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.6

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