本文選題：嗎啡 + 戒斷�。� 參考：《中國(guó)科學(xué)院研究生院（武漢物理與數(shù)學(xué)研究所）》2012年博士論文

【摘要】：長(zhǎng)期、多次使用阿片類藥物可誘導(dǎo)成癮行為,停藥后出現(xiàn)生理戒斷癥狀和心理渴求行為。在系統(tǒng)水平闡明參與戒斷反應(yīng)的腦區(qū),同時(shí)尋求有效抑制心理渴求行為的治療手段是目前成癮研究的重要目標(biāo)。 本文的主要研究?jī)?nèi)容為通過影像學(xué)、藥理學(xué)和行為學(xué)實(shí)驗(yàn)手段探討嗎啡誘導(dǎo)生理依賴和心理依賴的神經(jīng)基礎(chǔ)。在生理依賴的研究中,我們應(yīng)用錳離子增強(qiáng)磁共振成像(MEMRI)技術(shù)在系統(tǒng)水平探討參與嗎啡誘導(dǎo)的生理戒斷的易感腦區(qū)；在心理依賴的研究中,我們分別應(yīng)用藥理學(xué)和嗅覺損傷的方法探討有效抑制嗎啡誘導(dǎo)心理渴求的有效手段。本研究工作的目的：1)在系統(tǒng)水平確認(rèn)參與嗎啡誘導(dǎo)戒斷反應(yīng)的易感腦區(qū)；2)以嗎啡誘導(dǎo)的心理渴求過程谷氨酸系統(tǒng)功能紊亂為出發(fā)點(diǎn),以藥理學(xué)為主要研究手段,研究調(diào)整谷氨酸系統(tǒng)功能對(duì)心理渴求(條件化位置偏好,CPP)行為的影響,為新藥開發(fā)提供理論基礎(chǔ)；3)以硫酸鋅損傷嗅上皮為模型(ZnE),研究損傷嗅覺后對(duì)嗎啡誘導(dǎo)成癮行為的影響(包括行為敏感化和CPP行為)；4)以硫酸鋅損傷嗅上皮為干預(yù)環(huán)境刺激的手段,探討干擾環(huán)境刺激對(duì)心理渴求行為復(fù)發(fā)的影響,為破壞成癮線索刺激抑制心理渴求行為提供實(shí)驗(yàn)基礎(chǔ)。 論文第一章首先介紹了藥物成癮的神經(jīng)基礎(chǔ)理論、主要的理論假說和主要研究手段；然后綜述錳離子增強(qiáng)磁共振成像的原理及其在神經(jīng)系統(tǒng)研究中的主要應(yīng)用。 論文第二章主要是在系統(tǒng)水平探討參與嗎啡誘導(dǎo)生理戒斷期間易感腦區(qū)的研究。在該研究中,我們以錳離子增強(qiáng)磁共振成像(MEMRI)為主要技術(shù)手段,以嗎啡長(zhǎng)期遞增給藥誘導(dǎo)大鼠戒斷模型為研究對(duì)象,探討長(zhǎng)期使用嗎啡停藥后戒斷期間中樞神經(jīng)系統(tǒng)活性發(fā)生變化的主要腦區(qū),在系統(tǒng)水平尋找戒斷期間活性發(fā)生明顯變化的易感腦區(qū)。MEMRI結(jié)果顯示參與戒斷反應(yīng)的易感腦區(qū)包括扣帶皮層(Cg),運(yùn)動(dòng)皮質(zhì)(motor cortex),島葉皮質(zhì)(insular),海馬的CA1區(qū)(CA1)、CA2區(qū)(CA2)、CA3區(qū)(CA3)及齒狀回(DG),背側(cè)紋狀體(D-striatum),壓部皮質(zhì)(RS),伏隔核(NAc),杏仁核(Amy),外側(cè)下丘腦(PH),腹側(cè)被蓋區(qū)(VTA),上丘中央核(CIC),腹側(cè)紋狀體(V-striatum)和后外側(cè)下丘腦(LPH)等。這些腦區(qū)分布在多個(gè)系統(tǒng)中,主要集中在動(dòng)機(jī)系統(tǒng)(NAc),邊緣系統(tǒng)(Amy, VTA)和執(zhí)行系統(tǒng)(Cg),這些腦區(qū)可能是戒斷反應(yīng)的主要靶位點(diǎn)。 論文第三、四、五章主要內(nèi)容集中在嗎啡誘導(dǎo)心理渴求的藥理學(xué)和行為學(xué)研究。長(zhǎng)期使用嗎啡停藥后,谷氨酸系統(tǒng)亢進(jìn),用藥相關(guān)線索刺激能夠誘導(dǎo)成癮者產(chǎn)生心理渴求行為,在動(dòng)物研究中則表現(xiàn)為嗎啡誘導(dǎo)的CPP行為。在第三章中,我們探討小劑量MK-801和小劑量頭孢曲松聯(lián)合應(yīng)用抑制谷氨酸系統(tǒng)對(duì)嗎啡誘導(dǎo)條件化位置偏好(CPP)行為的影響。在實(shí)驗(yàn)研究中,以小劑量MK-801(0.05mg/kg, i.p.)與小劑量頭孢曲松(ceftriaxone,25mg/kg, i.p.)為復(fù)方制劑,探討抑制突觸后膜NMDA受體功能與提高膠質(zhì)細(xì)胞谷氨酸轉(zhuǎn)運(yùn)體-1(GLT-1)含量聯(lián)合作用對(duì)嗎啡誘導(dǎo)CPP行為的形成、消退和再建立的影響。研究結(jié)果表明單獨(dú)應(yīng)用小劑量MK-801(0.05mg/kg, i.p.),頭孢曲松(25mg/kg, i.p.)對(duì)嗎啡誘導(dǎo)CPP行為的形成、消退和再建立沒有影響。但是相同劑量MK--801和頭孢曲松組成復(fù)方制劑能夠抑制嗎啡誘導(dǎo)CPP的形成和再建立,(對(duì)消退行為沒有影響),同時(shí)實(shí)驗(yàn)中通過設(shè)立對(duì)照組排除小劑量復(fù)方制劑誘導(dǎo)動(dòng)物產(chǎn)生獎(jiǎng)賞或厭惡的可能,為進(jìn)一步開發(fā)新藥做了基礎(chǔ)性、理論性的工作。 論文第四章中,我們應(yīng)用鼻腔滴注硫酸鋅(ZnE)對(duì)小鼠進(jìn)行嗅覺剝奪處理,檢測(cè)嗅覺剝奪對(duì)嗎啡誘導(dǎo)成癮行為形成的影響。在嗎啡誘導(dǎo)成癮形成實(shí)驗(yàn)中,我們的研究結(jié)果發(fā)現(xiàn)ZnE處理能夠抑制嗎啡誘導(dǎo)敏感化的形成和CPP的形成,同時(shí)也抑制嗎啡誘導(dǎo)NAc內(nèi)FosB-樣蛋白的表達(dá),以上結(jié)果表明嗅覺剝奪處理能夠鈍化嗎啡效應(yīng),抑制嗎啡誘導(dǎo)的成癮行為。分析原因可能是ZnE處理后嗅覺功能受損,能夠抑制嗅覺線索與嗎啡效應(yīng)建立聯(lián)系產(chǎn)生的條件反射；另一方面ZnE處理不僅僅破壞嗅覺功能,對(duì)腦功能亦可能產(chǎn)生影響(嗎啡注射后NAc內(nèi)FosB-樣蛋白表達(dá)受到抑制),進(jìn)而影響嗎啡的作用。總之,以上結(jié)果表明嗅覺在嗎啡誘導(dǎo)成癮行為形成過程中發(fā)揮重要作用。 論文第五章中,我們應(yīng)用鼻腔滴注硫酸鋅(ZnE)對(duì)小鼠進(jìn)行嗅覺剝奪處理,然后檢測(cè)嗅覺剝奪對(duì)嗎啡誘導(dǎo)敏感化的表達(dá)和CPP再建立行為的影響。研究顯示ZnE處理能夠破壞嗎啡誘導(dǎo)敏感化的表達(dá)和CPP的再建立,同時(shí)也抑制嗎啡誘導(dǎo)敏感化期間NAc內(nèi)c-Fos的表達(dá)和CPP再建立期間多個(gè)成癮易感腦區(qū)內(nèi)c-Fos蛋白的表達(dá)。以上結(jié)果表明,在嗎啡誘導(dǎo)敏感化形成和CPP建立后,ZnE處理能夠抑制嗎啡誘導(dǎo)敏感化行為的表達(dá)和CPP再建立行為,破壞嗅覺刺激能夠抑制環(huán)境刺激誘發(fā)的復(fù)吸行為。
[Abstract]:For a long time, the use of opioids can induce addictive behavior, and there are physiological withdrawal symptoms and psychological craving after withdrawal. At the level of system, it is important to clarify the brain areas involved in the abstinence response and to seek effective measures to suppress the psychological craving.
The main content of this study is to explore the neural basis of morphine induced physiological dependence and psychological dependence by means of imaging, pharmacology and behavioral experiments. In the study of physiological dependence, we used manganese ion enhanced magnetic resonance imaging (MEMRI) to explore the susceptible brain regions of physiological withdrawal induced by morphine at a systematic level; In the study of psychological dependence, we applied the methods of pharmacology and olfactory injury to explore effective measures to effectively inhibit morphine induced psychological craving. The purpose of this study was to identify the susceptible brain regions involved in morphine induced withdrawal at the systematic level; 2) the dysfunction of glutamic acid system in the process of morphine induced psychological craving. For the starting point, the effects of the function of glutamic acid on the psychological craving (conditioned place preference, CPP) behavior were studied with pharmacology as the main research means, and the theoretical basis for the development of new drugs was provided. 3) the effect of zinc sulfate injury on the olfactory epithelium (ZnE) was used to study the effect of the morphine induced addiction (including behavioral sensitization) after the injury of the olfactory sense. And CPP behavior); 4) the effect of interfering environmental stimulation on the relapse of psychological craving was investigated by means of damaging the olfactory epithelium by zinc sulfate to interfere with the environmental stimulation, and the experimental basis was provided to destroy the addiction clue stimulation to suppress the psychological craving.
The first chapter first introduces the neural basis theory of drug addiction, the main theoretical hypothesis and the main research means, and then summarizes the principle of Mn ion enhanced MRI and its main application in the research of nervous system.
The second chapter of the thesis is the study of the susceptible brain regions involved in morphine induced physiological withdrawal. In this study, we used manganese ion enhanced magnetic resonance imaging (MEMRI) as the main technical means to study the long-term use of morphine induced withdrawal model in rats as the research object, and to explore the long-term use of morphine withdrawal during withdrawal. The main brain regions with changes in the activity of the central nervous system, the.MEMRI results in the brain region that have changed significantly at the level of systematic search for abstinence show that the susceptible brain regions involved in the withdrawal response include the cingulate cortex (Cg), the motor cortex (motor cortex), the insula cortex (insular), the CA1 region of the hippocampus (CA1), CA2 region (CA2), CA3 region (CA3) and teeth. DG, dorsal striatum (D-striatum), compression cortex (RS), nucleus accumbens (NAc), amygdala (Amy), lateral hypothalamus (PH), ventral tegmental area (VTA), central superior colliculus (CIC), ventral striatum (V-striatum) and posterolateral hypothalamus (LPH). These brain regions are distributed in multiple systems (NAc), marginal systems (Amy, and veins). And the execution system (Cg), these brain regions may be the main target sites for withdrawal reactions.
The third, fourth and five chapters mainly focus on the pharmacology and behavioral studies of morphine induced psychological craving. After long-term use of morphine, glutamate system hyperactivity and drug related clue stimulation can induce addicts to produce psychological craving. In animal studies, the morphine induced CPP behavior. In the third chapter, we explore The effect of the combination of small dose MK-801 and small dose of ceftriaxone on morphine induced conditioned position preference (CPP) behavior was investigated. In the experimental study, a small dose of MK-801 (0.05mg/kg, i.p.) and small dose ceftriaxone (ceftriaxone, 25mg/kg, i.p.) were used as compound preparations to investigate the inhibition of the function and extraction of the postsynaptic membrane NMDA receptor. The effect of the combined effect of glutamate transporter -1 (GLT-1) on the formation, regression and re establishment of morphine induced CPP behavior. The results showed that small doses of MK-801 (0.05mg/kg, i.p.), 25mg/kg, i.p. (25mg/kg, i.p.) were used to induce the formation of CPP in morphine, and the regression and re establishment did not affect the formation of morphine, but the same dose of MK-- was not affected. 801 and ceftriaxone compound preparation can inhibit the formation and reestablishment of morphine induced CPP, (no effect on the withdrawal behavior). At the same time, the possibility of inducing animals to produce reward or disgust by setting up a control group is set up in the control group, and the basic and theoretical work is made for the further development of new drugs.
In the fourth chapter, we used a nasal drip of zinc sulfate (ZnE) to detect the effect of olfactory deprivation on the formation of morphine induced addiction in mice. In the formation of morphine induced addiction, we found that ZnE treatment could inhibit the formation of morphine induced sensitization and the formation of CPP, and also inhibit the formation of morphine induced sensitization. Morphine induced the expression of FosB- like protein in NAc. The above results show that olfactory deprivation treatment can passivate morphine effect and inhibit morphine induced addiction. The reason may be that the olfactory function is damaged after ZnE treatment and can inhibit the conditioned reflex caused by the establishment of the olfactory clue and morphine effect; on the other hand, the ZnE treatment is not only broken. The bad olfactory function may also affect the function of the brain (the expression of FosB- like protein in NAc after morphine injection is inhibited) and then affects the effect of morphine. All in all, the above results show that olfactory plays an important role in the formation of morphine induced addiction behavior.
In the fifth chapter, we use the nasal drip of zinc sulfate (ZnE) to treat the mice with olfactory deprivation, and then detect the effect of olfactory deprivation on the expression of morphine induced sensitization and the reestablishment of CPP. The study shows that ZnE treatment can destroy the expression of morphine induced sensitization and the reestablishment of CPP, and also inhibit the induced sensitization of morphine. The expression of c-Fos in NAc and the expression of c-Fos protein in a number of susceptible brain regions during the period of reestablishment of CPP. The above results show that after the formation of morphine induced sensitization and the establishment of CPP, ZnE treatment can inhibit the expression of morphine induced sensitization behavior and CPP reestablishment behavior, and the destruction of olfactory stimulation can inhibit the relapse induced by environmental stimulation. Yes.

【學(xué)位授予單位】：中國(guó)科學(xué)院研究生院（武漢物理與數(shù)學(xué)研究所）
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.61

【共引文獻(xiàn)】

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