重复吗啡注射诱导生理戒断和心理渴求的神经影像学与行为学研究

发布时间：2018-04-25 13:22

本文选题：吗啡 + 戒断　；参考：《中国科学院研究生院（武汉物理与数学研究所）》2012年博士论文

【摘要】：长期、多次使用阿片类药物可诱导成瘾行为,停药后出现生理戒断症状和心理渴求行为。在系统水平阐明参与戒断反应的脑区,同时寻求有效抑制心理渴求行为的治疗手段是目前成瘾研究的重要目标。本文的主要研究内容为通过影像学、药理学和行为学实验手段探讨吗啡诱导生理依赖和心理依赖的神经基础。在生理依赖的研究中,我们应用锰离子增强磁共振成像(MEMRI)技术在系统水平探讨参与吗啡诱导的生理戒断的易感脑区；在心理依赖的研究中,我们分别应用药理学和嗅觉损伤的方法探讨有效抑制吗啡诱导心理渴求的有效手段。本研究工作的目的：1)在系统水平确认参与吗啡诱导戒断反应的易感脑区；2)以吗啡诱导的心理渴求过程谷氨酸系统功能紊乱为出发点,以药理学为主要研究手段,研究调整谷氨酸系统功能对心理渴求(条件化位置偏好,CPP)行为的影响,为新药开发提供理论基础；3)以硫酸锌损伤嗅上皮为模型(ZnE),研究损伤嗅觉后对吗啡诱导成瘾行为的影响(包括行为敏感化和CPP行为)；4)以硫酸锌损伤嗅上皮为干预环境刺激的手段,探讨干扰环境刺激对心理渴求行为复发的影响,为破坏成瘾线索刺激抑制心理渴求行为提供实验基础。论文第一章首先介绍了药物成瘾的神经基础理论、主要的理论假说和主要研究手段；然后综述锰离子增强磁共振成像的原理及其在神经系统研究中的主要应用。论文第二章主要是在系统水平探讨参与吗啡诱导生理戒断期间易感脑区的研究。在该研究中,我们以锰离子增强磁共振成像(MEMRI)为主要技术手段,以吗啡长期递增给药诱导大鼠戒断模型为研究对象,探讨长期使用吗啡停药后戒断期间中枢神经系统活性发生变化的主要脑区,在系统水平寻找戒断期间活性发生明显变化的易感脑区。MEMRI结果显示参与戒断反应的易感脑区包括扣带皮层(Cg),运动皮质(motor cortex),岛叶皮质(insular),海马的CA1区(CA1)、CA2区(CA2)、CA3区(CA3)及齿状回(DG),背侧纹状体(D-striatum),压部皮质(RS),伏隔核(NAc),杏仁核(Amy),外侧下丘脑(PH),腹侧被盖区(VTA),上丘中央核(CIC),腹侧纹状体(V-striatum)和后外侧下丘脑(LPH)等。这些脑区分布在多个系统中,主要集中在动机系统(NAc),边缘系统(Amy, VTA)和执行系统(Cg),这些脑区可能是戒断反应的主要靶位点。论文第三、四、五章主要内容集中在吗啡诱导心理渴求的药理学和行为学研究。长期使用吗啡停药后,谷氨酸系统亢进,用药相关线索刺激能够诱导成瘾者产生心理渴求行为,在动物研究中则表现为吗啡诱导的CPP行为。在第三章中,我们探讨小剂量MK-801和小剂量头孢曲松联合应用抑制谷氨酸系统对吗啡诱导条件化位置偏好(CPP)行为的影响。在实验研究中,以小剂量MK-801(0.05mg/kg, i.p.)与小剂量头孢曲松(ceftriaxone,25mg/kg, i.p.)为复方制剂,探讨抑制突触后膜NMDA受体功能与提高胶质细胞谷氨酸转运体-1(GLT-1)含量联合作用对吗啡诱导CPP行为的形成、消退和再建立的影响。研究结果表明单独应用小剂量MK-801(0.05mg/kg, i.p.),头孢曲松(25mg/kg, i.p.)对吗啡诱导CPP行为的形成、消退和再建立没有影响。但是相同剂量MK--801和头孢曲松组成复方制剂能够抑制吗啡诱导CPP的形成和再建立,(对消退行为没有影响),同时实验中通过设立对照组排除小剂量复方制剂诱导动物产生奖赏或厌恶的可能,为进一步开发新药做了基础性、理论性的工作。论文第四章中,我们应用鼻腔滴注硫酸锌(ZnE)对小鼠进行嗅觉剥夺处理,检测嗅觉剥夺对吗啡诱导成瘾行为形成的影响。在吗啡诱导成瘾形成实验中,我们的研究结果发现ZnE处理能够抑制吗啡诱导敏感化的形成和CPP的形成,同时也抑制吗啡诱导NAc内FosB-样蛋白的表达,以上结果表明嗅觉剥夺处理能够钝化吗啡效应,抑制吗啡诱导的成瘾行为。分析原因可能是ZnE处理后嗅觉功能受损,能够抑制嗅觉线索与吗啡效应建立联系产生的条件反射；另一方面ZnE处理不仅仅破坏嗅觉功能,对脑功能亦可能产生影响(吗啡注射后NAc内FosB-样蛋白表达受到抑制),进而影响吗啡的作用。总之,以上结果表明嗅觉在吗啡诱导成瘾行为形成过程中发挥重要作用。论文第五章中,我们应用鼻腔滴注硫酸锌(ZnE)对小鼠进行嗅觉剥夺处理,然后检测嗅觉剥夺对吗啡诱导敏感化的表达和CPP再建立行为的影响。研究显示ZnE处理能够破坏吗啡诱导敏感化的表达和CPP的再建立,同时也抑制吗啡诱导敏感化期间NAc内c-Fos的表达和CPP再建立期间多个成瘾易感脑区内c-Fos蛋白的表达。以上结果表明,在吗啡诱导敏感化形成和CPP建立后,ZnE处理能够抑制吗啡诱导敏感化行为的表达和CPP再建立行为,破坏嗅觉刺激能够抑制环境刺激诱发的复吸行为。
[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.

【学位授予单位】：中国科学院研究生院（武汉物理与数学研究所）
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.61

【共引文献】