阿片类物质心瘾形成相关证候及神经生物学机制研究
摘要
随着外源性阿片类物质滥用成为世界性公害,我国阿片类物质滥用人数也正在不断激增,阿片类药物成瘾是一种慢性反复发作性脑病,已成为目前社会及医学领域的一大问题,其戒断复杂而艰难。近二十年来大量学者对成瘾的机制、戒断方法等各个方面进行了深入的研究,因此实现脱毒并无困难,对脱毒后急性戒断综合征也形成了有效的综合治疗措施,稽延性戒断综合征中的躯体依赖症状也逐步实现了针对性治疗,目前考验戒毒工作的最大难题是阿片类物质引起的心理渴求,中医称之为“心瘾”,这是戒断后复发率高居不下的关键,目前现代医学和中医学均尚无有效的处理措施。
辨证论治是中医学的一个基本特点,辨证之所以重要就在于“证”是中医治疗的首要依据,在祖国医学几百年的戒毒医疗实践中,对心瘾的病因病机及辨证分型都有所记载,然而都只限于个人的经验探讨,尚无客观化研究成果,也未形成系统的理论体系,成为中医治疗心瘾的桎梏。
基于目前现代医学无药可治,中医学无证可辨的研究现状,本课题以阿片类物质心瘾立题,通过理论研究和实验客观研究相结合的方法对心瘾相关证候进行探讨,以期使阿片类物质心瘾有证可辨,辨证客观,对中医临床用药作出一定贡献。
论文分为理论研究和实验研究两部分:理论研究部分在大量文献分析基础上,综合运用演绎、类比、引证等方法,分别从脏腑失调和痰浊内停两个方面,对阿片类物质戒断症状的相关机制进行分析,深入探讨了阿片类物质心瘾相关病机及证候。实验部分结合既往研究,采用以方测证的方法对理论结论进行验证,各个证型针对方是结合大量临床证候学调查,将课题组所用的临床有效方虎门合剂化裁而成,分为四个组方,补肾方、疏肝方、养心方和化痰方。继而在病证结合研究思路的指导下,对阿片类物质心瘾模型中各个证型的神经生物学机制进行研究,现代研究表明伏核、前额叶皮质是心瘾形成密切相关脑区,其突触可塑性变化是心瘾的根本病机,因此本实验对心瘾形成相关证候与两脑区突触可塑性相关蛋白的关系为切入点探讨相关证候的病理基础。
研究一阿片类物质成瘾形成相关证候的理论研究
理论研究一从脏腑功能失调论阿片类物质成瘾
方法:本研究通过大量古代及现代文献分析,运用归纳法将阿片类物质成瘾所导致的各类急性戒断症状和稽延性戒断症状与脏腑功能失调的关系进行分析,发现各类症状中,仅对心瘾尚未提出当从何脏腑论治。因此以心瘾形成的核心机制“动机异常”为切入点,结合大量文献研究,采用类比法、演绎法对阿片类物质心瘾形成与脏腑失调的关系进行深入探讨。结果:阿片类物质心瘾形成是“肝主疏泄”、“肝司谋虑”、“肾藏志”等肝肾功能失调的结果。结论:阿片类物质心瘾作为一种情志疾病,其形成的核心证候基础为“肝失疏泄”,也与肾之阴阳不足相关。
理论研究二痰浊内阻与阿片类物质成瘾的关系
方法:结合文献研究,对“痰”的产生机制、致病特性进行探讨,并采用类比法、演绎法对“痰”这一病理产物与阿片类物质心瘾持续顽固存在的关系进行探讨。结果:“痰”是在疾病发展进程中形成的一种病理产物,同时又作为一种致病因素对疾病产生影响,阿片类物质心瘾持续顽固的特性与“痰”的致病特点极为吻合。结论:痰浊的形成是阿片类物质依赖发展到一定程度的结果,“痰”是心瘾持续顽固的主要病因。
以此为基础提出本研究的理论结论:阿片物质成瘾中各类急性戒断症状和稽延性戒断症状分别与不同脏腑的功能失调相关,其中阿片类物质心瘾形成核心相关证候为“肝失疏泄”,与肾阴阳两虚也密切相关;另外,当阿片类物质成瘾发展到一定阶段会导致痰浊内停,成为心瘾持续顽固的证候基础。在实验研究中,对心瘾形成相关证候进一步验证,并探讨的其病理机制。
研究二阿片类物质心瘾形成相关证候及神经生物学基础研究
实验研究一阿片类物质心瘾动物模型的优化和评价
方法:本研究在条件位置偏爱经典模型的基础上,结合本实验室的NODULE公司行为学研究装置建立了条件位置偏爱自动观察分析系统,根据非倾向性实验设计的原理采用非自然偏爱箱白箱为伴药箱,并在本实验室条件下,分别采用5mg/kg、10mg/kg和15mg/kg连续10天皮下注射吗啡的方法对大鼠进行条件位置训练50min,对照组大鼠仅注射生理盐水。训练结束后,进行条件位置偏爱测试15min。结果:条件位置偏爱自动观察分析系统对吗啡诱导的条件位置偏爱行为进行了实时记录和模式化分析,三种吗啡剂量训练50min均能使大鼠产生条件性位置偏爱,但相比之下,10mg/kg和15mg/kg的吗啡用量所产生的位置偏爱要更加明显,但15mg/kg的吗啡用量大鼠易激惹,且活动性差。结论:条件位置偏爱自动观察系统对吗啡诱导的条件位置偏爱行为进行实时记录和模式化分析,排除了非条件环境的干扰因素,具有精确、客观的优点,这在动物行为学观测中具有非常重要的意义。10mg/kg皮下注射为最佳吗啡诱导剂量,既能产生明显的条件位置偏爱效应,操作性也最强。在进一步的实验中,采用本实验心瘾模型的优化方案:非倾向性实验设计,皮下注射吗啡10mg/kg,训练时间为50min,连续造模10天,训练结束后进行测试15min,在自动观察系统中进行观察分析。
实验研究二以方测证探讨心瘾形成相关中医证候
方法:采用实验一的优化方案建立条件位置偏爱模型,结合所在课题组前期临床证候调查结果,将临床实践抗复吸有效方虎门合剂化裁为补肾方、疏肝方、化痰方和养心方,采用以方测证的方法,观察各个证型针对方对条件位置偏爱的改善作用,进而对理论结论中心瘾形成相关证候进行验证。结果:与心瘾模型组相比,补肾组和疏肝组大鼠在伴药箱中的停留时间显著下调(P＜0.05),化痰组在伴药箱内的停留时间虽有下调趋势,但无显著差异,而养心组的大鼠在伴药箱的停留时间无变化。结论:补肾方、疏肝方对吗啡诱导的条件位置偏爱行为有所改善,养心方无显著改善,通过行为学进一步验证了理论结论,肝失疏泄、肾阴阳两虚是阿片类物质心瘾形成的证候基础。而化痰方表现出对条件位置偏爱行为有所改善但无显著差异的原因可能与造模的时间、造模的方式所代表的疾病进程有一定关系,有待进一步研究。
实验研究三心瘾形成相关中医证候与Syp的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区Syp的阳性反应物、蛋白表达量和mRNA表达水平。结果:免疫组化结果显示在前额叶皮质和伏核中,Syp免疫阳性产物呈棕黄色,分布在胞浆中,各组阳性反应物无显著差异。Western blot结果显示,与对照组相比,伏核中模型组Syp蛋白表达显著升高(P＜0.05);前额叶皮质中Syp蛋白表达差异不具有显著性。与模型组相比,伏核中补肾组和疏肝组Syp蛋白表达显著下调(P＜0.05),而前额叶皮质中Syp蛋白表达无显著差异。其它组方无显著调节作用。Real time PCR结果显示,与对照组相比,伏核和前额叶皮质中模型组Syp的mRNA表达均无显著差异。与模型组相比,伏核和前额叶皮质中,补肾组Syp的mRNA表达均无显著差异,伏核中疏肝组Syp的mRNA表达显著下调(P＜0.05),前额叶皮质中疏肝组Syp的mRNA表达无显著差异。结论:在阿片类物质心瘾模型中,伏核中Syp的蛋白表达的上调与阿片类物质心瘾的形成相关。补肾方能显著下调Syp蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调,养心方和化痰方没有明显疗效。进一步验证了阿片类心瘾的形成在肝肾而不在心,也表明肝肾功能与高级中枢系统突触塑性密切相关,其失调的机制之一为伏核中与突触可塑性密切相关的Syp蛋白表达的异常,更深层次的机制有待进一步研究。
实验研究四心瘾形成相关中医证候与NMDA受体调节亚基的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区NMDA调节亚基NR2A、NR2B的阳性反应物、蛋白表达量和mRNA表达水平。结果:对NR2A,免疫组化和Western blot结果显示,在伏核和前额叶皮质中,模型组中NR2A免疫染色阳性神经元数及蛋白表达变化不显著,各个组方对NR2A的表达无显著调节作用。对于NR2B,免疫组化结果显示,与对照组相比,伏核和前额叶皮质中模型组NR2B阳性神经元数均显著上升(P＜0.05)。与模型组相比,伏核中补肾组NR2B阳性神经元数显著下调(P＜0.05),前额叶皮质中补肾组NR2B阳性神经元数无显著变化;与模型组相比,伏核和前额叶皮质中,疏肝组NR2B阳性神经元数显著下调(P＜0.05)。其他组方无明显的调节作用。Western blot结果显示,与对照组相比,伏核中模型组NR2B蛋白表达极显著升高(P＜0.01);前额叶皮质中NR2B蛋白表达显著升高(P＜0.05)。与模型组相比,补肾组和疏肝组伏核和前额叶皮质中NR2B蛋白表达均显著下调(P＜0.05),但与对照组相比,补肾组伏核中NR2B蛋白表达仍显著较高(P＜0.05)。其它组方无显著调节作用。Real time PCR结果显示,与对照组相比,伏核中模型组NR2B的mRNA表达极显著升高(P＜0.01),前额叶皮质mRNA表达也显著升高(P＜0.05)。与模型组相比,伏核和前额叶皮质中疏肝组NR2B的mRNA表达显著下调(P＜0.05)。其它组方无显著调节作用。结论:伏核和前额叶皮质中,NR2A调节亚基表达水平与阿片类物质心瘾的形成无显著相关,NR2B蛋白和基因水平的改变可能是阿片类物质心瘾形成的分子机制之一。在伏核和前额叶皮质中补肾方能显著下调NR2B蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调,再一次证明阿片类物质心瘾形成的主要病机是肝肾失调的同时,表明肝失疏泄的神经生物学本质与NR2B调节亚基在蛋白和基因水平的失调有关;肾阴阳不足的本质与NR2B蛋白表达水平的失调关系更为密切。
实验研究五心瘾形成相关中医证候与BDNF的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区BDNF的阳性反应物、蛋白表达量和mRNA表达水平。结果:免疫组化结果显示,与对照组相比,伏核中模型组BDNF阳性神经元数极显著升高(P＜0.01),前额叶皮质中模型组BDNF阳性神经元数也显著升高(P＜0.05)。与模型组相比,伏核和前额叶皮质中,补肾组和疏肝组BDNF阳性神经元数均显著下调(P＜0.05),但与对照组比较,疏肝组伏核中BDNF神经元仍显著较高(P＜0.05)。其他组方无显著调节作用。Western blot结果显示,与对照组相比,伏核和前额叶皮质中,模型组BDNF蛋白表达显著升高(P＜0.01)。与模型组相比,伏核补肾组和疏肝组BDNF蛋白表达显著下调(P＜0.05),而前额叶皮质中BDNF蛋白表达极显著下调(P＜0.01)。Real time PCR结果显示,与对照组相比,伏核和前额叶皮质中模型组BDNF的mRNA表达均极显著升高(P＜0.01)。与模型组相比,伏核和前额叶皮质中疏肝组BDNF的mRNA表达显著下调(P＜0.05),但与对照组比较,前额叶皮质中BDNF mRNA表达仍显著升高(P＜0.05)。结论:伏核和前额叶皮质中,BDNF蛋白表达和mRNA表达的升高均与阿片类物质心瘾的形成相关,表明BDNF蛋白和基因水平的改变可能是阿片类物质心瘾形成的分子机制之一。对于BDNF蛋白和基因水平的调节作用,在伏核和前额叶皮质中补。肾方能显著下调其蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调。表明“肝失疏泄”的神经生物学本质与BDNF在蛋白和基因水平的失调有关;肾阴阳不足的本质仅与BDNF蛋白表达水平的失调关系更为密切。结合对NR2B及Syp的研究,认为阿片类物质心瘾的中医病机主要责之于肝肾,因此本研究结果进一步扩展了肝肾的本质在现代神经生物学中的外延,在中枢神经系统内,肝失疏泄与动机系统的突触可塑性改变相关,本研究可见伏核和前额叶皮质中可塑性相关蛋白在基因和蛋白水平的失调;而肾虚则主要与前额叶皮质和伏核中突触可塑性相关指标在蛋白水平的失调有关。
本研究在经典条件位置偏爱模型的基础上,利用本实验室新引进的NODULE公司行为学研究装置建立自动化条件位置偏爱观察分析系统,从而减少了非条件环境因素对吗啡相关条件线索的干扰,对不同剂量吗啡引起的条件位置偏爱效应进行比较,从而结合现代行为学手段,使阿片类物质心瘾模型进一步优化。采用演绎法、类比法及引证法等对阿片类物质心瘾相关的证候进行理论研究,在此基础上,将临床抗戒断有效方虎门合剂化裁为四个证型针对方,进一步采用以方测证的方法进行了行为学验证,对阿片类物质心瘾形成相关证候提出:心瘾形成的主要证候基础是“肝失疏泄”,同时肾之阴阳不足对心瘾的形成也有重要影响。对阿片类物质心瘾的神经生物学本质进行了探讨,结合伏核、前额叶皮质的突触可塑性在阿片类物质心瘾与异常用药动机形成的关系,以及Syp、NR2B亚基和BDNF三个蛋白与突触可塑性、心瘾的关系,本研究认为阿片类物质心瘾的形成与伏核和前额叶皮质中NR2B和BDNF的基因和蛋白水平的升高,伏核中Syp的蛋白水平升高相关。在病证结合的研究思路指导下,对阿片类物质心瘾相关证候的神经生物学本质进行了探讨,本研究认为心瘾形成相关肝失疏泄证的现代生物学本质为Syp、NR2B和BDNF在蛋白和基因水平的失调引起的伏核和前额叶皮质的突触可塑性变化;而肾阴阳不足的本质则在于以上三个指标在蛋白水平失调引起的上述脑区突触可塑性变化。通过上述研究,本研究对肝肾本质有更进一步的认识,在既往研究将“肝肾同源于精血”推进到“肝肾同源于脑”的基础上,又进一步扩展到“肝肾同源于动机回路”。
Along with the exogenous opioid abuse becomes the public disruption in the world,in China the abusers is increasing sharply.Drug addiction is a chronic and recurrent encephalopathy,which is difficult to solve in modern medicine.Over the last 20 years,due to the general research in the pathogenesis and the therapeutics to drug abuse,detoxification can be cured completely,and the acute withdrawal syndrome,protracted physical dependence can be treated directly too.But the obsessive drug-craving,the main reason for relapse,is the hang-up to cure the drug addiction radically.
The treatment based on syndrome differentiation is the characteristic of the Chinese medicine.Drug abuse is treated for hundreds of years by Chinese medicine,but the cognitions about the etiopathogenisis and pathogenesis are only confined to personal experiences,which is the shackle to treat craving objectively and systematically.
To cure drug-craving in modern medicine and Chinese medicine,the study on syndrome of drug craving systematically and objectively is necessary.The research explores the syndrome differentiation of drug craving in both theory and experiment,which will afford objective evidence and systematical theory to guide the treatment of drug craving in clinic.
The thesis contains theoretical and the experimental study:in the theoretical part, deduction,analogism and the citation were used to elicit the hypothesis on the pathogenesis and syndrome of drug-craving;in the experimental part,the method to detect the syndrome by formula was used to certify the hypothesis.First,according to the research of syndromes for years clinically,the effective formula to prevent relapse,named "hu men he ji" was divided into four sub-formulas aiming at different syndromes,called "invigorating the kidney formula" "dispersing the depressed liver-energy formula" "dissipating phlegm formula" and "supporting heart formula".And then we assessed the syndromes by detecting the effect of the above sub-formulas to conditioned place preference induced by morphine and analyzed pathogenesis of related syndromes,for the nucleus accumbens(NAc) and Cortex of frontal lobe(PFC) are the crucial encephalic regions in drug addiction,and the synaptic plasticity is the fundamental pathogenesis of drug-craving,the analysis focused on the relation between the drug-craving and the synaptic plasticity in NAc and PFC.
PartⅠThe theoretical study on the syndromes of drug-craving Theoretical study one:the relation between entrails and drug addiction
Method:By literature study,the relation between all kinds of withdrawal symptoms and functional disorder of entrails was analyzed by induction,and the related organs to drug-craving was unkown,together with the core mechanism of drug-craving,analogism,deduction,and citation were used to analyze the relation between the "liver controlling dispersion" and the formation of drug-craving.And the relation between "liver managing deliberation" "kidney controlling aspiration" and the formation of drug-craving is analyzed by deduction,and citation too.Result:The formation of drug-craving is the result of functional disorder of "liver controlling dispersion" "liver managing deliberation" and "kidney controlling aspiration".Conclusion:Drug-craving is an emotional disease,the core syndrome of which is "liver failing to control dispersion",and other related syndromes are "Yin and Yang deficiency of kidney".
Theoretical study two:Phlegm should be responsible for persistence of drug-craving
Method:By literature study,the production and morbigenous characteristic were analyzed,analogism and deduction were used to analyze the relation between the pathogen of phlegm and the persistence of drug-craving.Result:Phlegm is a patho-product of diseases, which influences the disease as a pathogen too.The persistence of drug-craving coincides with the morbigenous characteristics of phlegm.Conclusion:The phlegm,which resulted from drug addiction,is the main reason for the persistence of drug-craving.
The conclusion of theoretical part:Different withdrawal symptoms are related to different entrails,and the core syndrome of fonnation of drug-craving is "liver failing to control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney". The phlegm,which resulted from drug addiction,is the main reason for the persistence of drug-craving.In experimental study,the theoretical conclusion will be verified further.
PartⅡThe experimental study on the syndromes of drug-craving Experiment one:Optimization and evaluation of the conditioned place preference
Method:Based on the classical conditioned place preference(CPP),automatic test system of CPP was set up to make use of the behavioral equipment and software from NODULE corporation.According to unbiased design,white compartment was designed as the morphine-paired compartment.Morphine(5mg/kg,10mg/kg,or 15mg/kg,i.p.) was separately administrated in white compartment and saline on the other side.In control group,0.9% sodium chloride(10mg/kg,i.p.) was administrated on both sides.Conditioning consisted of 50-min sessions,and testing was for 15min.Result:Real-time recording and hipping analysis to CPP came true in the automatic test system.CPP could be induced successfully by morphine of the above three doses.CPP induced by morphine of 10mg/kg and 15mg/kg were more obvious,but rats injected by morphine of 15mg/kg showed irritability and low reactiveness,so the 10mg/kg was optimized dose for CPP in the study.Conclusion:The automatic test system of CPP are more accurate and objective,for it can make real-time recording and hipping analysis to behavior,and eliminate the disturbance of unconditioned clues.10mg/kg is the optimized dose to induce the CPP by i.p..The above optimized scheme will be used in further study.
Experiment two:the relation between the malfunction of liver and kidney and the formation for drug craving
Method:The optimized design by experiment one was used to set up the CPP.Method to detect the syndrome by formula were used to certify the theoretical study.According to clinical study on syndromes of opiod dependence for years,the effective formula to prevent relapse,named "hu men he ji" were divided into four sub-formulas aiming at different syndromes,called "invigorating the kidney formula" "dispersing the depressed liver-energy formula" "dissipating phlegm formula" and "supporting heart formula".And then modulation of the four formulas to rewarding effect in CPP induced by morphine was detected.Result: The time staying in white compartment of model group was significantly longer than that of control(P＜0.01).Compared to model group,the time staying in white compartment of both "invigorating the kidney group" and "dispersing the depressed liver-energy group" was significantly reduced(P＜0.01).And the mean time staying in white compartment of dissipating phlegm group reduced too,but there was no significant difference to the model group,and the supporting heart formula had no effect.Conclusion:"invigorating the kidney formula" and "dispersing the depressed liver-energy formula" can alter the CPP induced by morphine,together with the previous study,"liver failing to control dispersion" is considered as the core syndrome of the formation of drug-craving,and other related syndrome is the "Yin and Yang deficiency of kidney".
Experiment three:The relation between synaptophysin and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:In immunohistochemistry,in NAc and PFC the synaptophysin's positive products were buffer granules,which distributed in cytoplasm,and had no significant difference in each group.In western blot,compared to control group,the protein of synaptophysin of model group increased in NAc(P＜0.05),but not in PFC.Compared to model group,in NAc the protein of synaptophysin of the invigorating kidney group and the invigorating liver group decreased significantly(P<0.05), and had no chang in PFC.No significant differences were found in other groups.In real time PCR,there was no significant difference between control group and model group.But compared to the model group,the expression of synaptophysin's mRNA were down-regulated in invigorating liver group in NAc(P<0.05),and had no difference in other encephalic region. Conclusion:In the study,synaptophysin,related to synaptic plasticity,is up-regulated in NAc, so it probably is a main reason for drug-craving,but the further pathology still need be studied. Invigorating kidney formula can down-regulate the protein of synaptophysin,and the invigorating liver formal can down regulate both the protein and the gene expression,and other formulas have no effect.The above proves the theoretical study that the kidney and liver, but not heart,should be responsible for formation of drug-craving,and the dysfunction of kidney and liver is correlated to the synaptic plasticity due to the increase of the synaptophysin in the NAc.
Experiment four:The relation between regulatory subunit of NMDA receptor and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:NR2A and NR2B regulatory subunit were studied.In immunohistochemistry,in NAc and PFC,NR2A's positive products had no significant difference in each group.Compared to control group,NR2B's positive products increased in both NAc and PFC(P<0.05),and compared to model group, invigorating kidney formula down-regulated NR2B's positive products in NAc(P<0.05), invigorating liver group down-regulated NR2B's positive products in both NAc and PFC(P<0.05),other formulas didn't have effect.In Western blot,compared to control group, the protein of NR2B increased significantly in NAc(P<0.01),and increased in PFC too(P<0.05).Compared to model group,invigorating kidney and invigorating liver formulas could down-regulate the protein of NR2B in both NAc and PFC(P<0.05),but still higher than the control group in NAc in invigorating kidney group(P<0.05).In real time PCR,compared to the control group,the expression of mRNA of NR2B increased significantly in NAc(P<0.01),and increased in PFC too(P<0.05).Compared to model group,invigorating liver formula could down regulate expression of mRNA in both NAc and PFC(P<0.05).Conclusion:in NAc and PFC,the change of NR2B in protein and gene level is related to the formation of drug-craving,not NR2A.In NAc and PFC,invigorating kidney formula can down-regulate the protein of NR2B,and invigorating liver formula can down-regulate both protein and gene of NR2B,Other formulas had no effect.The experiment proves that the kidney and liver should be responsible for drug-craving,but not heart,which means the pathology of drug-craving is the dysfunction of kidney and liver.The essence of "liver failing to control dispersion" is the up-regulation of NR2B in both protein and gene level,and "Yin and Yang deficiency of kidney" is due to the up-regulation of NR2B in protein level.
Experiment five:The relation between BDNF and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:In immunohistochemistry, compared to the control group,in NAc the reactive products of BDNF increased significantly in model group(P＜0.01),and in PFC the products increased too(P＜0.05).Compared to model group,in both NAc and PFC,invigorating kidney and invigorating liver formulas could down-regulate the reactive products(P＜0.05),but the products of invigorating liver group were still higher than the control group(P＜0.05).Other formulas had no effect.In western blot, compared to the control group,in NAc and PFC,the protein of BDNF increased significantly(P＜0.01).And compared to model group,in NAc invigorating kidney and invigorating liver groups down-regulated the protein of BDNF(P＜0.05),and in PFC down-regulated the protein remarkably(P＜0.01).In real time PCR,compared to the control group,in model group the gene expression of BDNF increased significantly(P＜0.01). Compared to model group,in NAc and PFC,invigorating liver formula could down-regulate the gene expression of BDNF(P＜0.05),but in PFC the gene expression of BDNF was still higher than control group(P＜0.05).Conclusion:In NAc and PFC,the increase of protein and gene of BDFN is related to the formation of drug-craving,which represents dysfunction of BDNF is probably the main reason of drug-craving.And in NAc and PFC,invigorating kidney formula only can down-regulate the protein of BDNF,but invigorating liver formula can regulate in both protein and gene level.Along with the experiment about synaptophysin and NMDA receptors,the research verify that the core syndrome of the formation of drug-craving is "liver failing to control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney",whose neurobiology essence is the synaptic plasticity due to dysfunction of related proteins like synaptophysin,NR2B and BDNF in PFC and NAc.
The research makes breakthrough in five sides:first,based on the classical CPP, automatic test system of CPP is set up to make use of the behavioral equipment and software from NODULE corporation,which are more accurate and objective,for it can make real-time recording and hipping analysis to behavior,and eliminate the disturbance of unconditioned clues.Second,provide theoretical conclusion to syndromes of drug-craving by deduction, citation and analogism,and then use formulas to verify that the core syndrome of the formation of drug-craving is "liver failing to Control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney".Third,the neurobiology essence of drug-craving is considered as the increase of NR2B and BDNF in both protein and gene level in PFC and NAc,and also related to increase of synaptophysin in protein level only in NAc.Four,the neurobiology essence of "liver failing to control dispersion" in formation of drug-craving is the synaptic plasticity due to dysfunction of related proteins such as synaptophysin,NR2B and BDNF in PFC and NAc in both protein and gene level,and "Yin and Yang deficiency of kidney" due to the dysfunction of the above in protein level.And above that,the research expand the essence of the kidney and liver that the two ZANG-organs are related to motive circuit in nerve center.
辨证论治是中医学的一个基本特点,辨证之所以重要就在于“证”是中医治疗的首要依据,在祖国医学几百年的戒毒医疗实践中,对心瘾的病因病机及辨证分型都有所记载,然而都只限于个人的经验探讨,尚无客观化研究成果,也未形成系统的理论体系,成为中医治疗心瘾的桎梏。
基于目前现代医学无药可治,中医学无证可辨的研究现状,本课题以阿片类物质心瘾立题,通过理论研究和实验客观研究相结合的方法对心瘾相关证候进行探讨,以期使阿片类物质心瘾有证可辨,辨证客观,对中医临床用药作出一定贡献。
论文分为理论研究和实验研究两部分:理论研究部分在大量文献分析基础上,综合运用演绎、类比、引证等方法,分别从脏腑失调和痰浊内停两个方面,对阿片类物质戒断症状的相关机制进行分析,深入探讨了阿片类物质心瘾相关病机及证候。实验部分结合既往研究,采用以方测证的方法对理论结论进行验证,各个证型针对方是结合大量临床证候学调查,将课题组所用的临床有效方虎门合剂化裁而成,分为四个组方,补肾方、疏肝方、养心方和化痰方。继而在病证结合研究思路的指导下,对阿片类物质心瘾模型中各个证型的神经生物学机制进行研究,现代研究表明伏核、前额叶皮质是心瘾形成密切相关脑区,其突触可塑性变化是心瘾的根本病机,因此本实验对心瘾形成相关证候与两脑区突触可塑性相关蛋白的关系为切入点探讨相关证候的病理基础。
研究一阿片类物质成瘾形成相关证候的理论研究
理论研究一从脏腑功能失调论阿片类物质成瘾
方法:本研究通过大量古代及现代文献分析,运用归纳法将阿片类物质成瘾所导致的各类急性戒断症状和稽延性戒断症状与脏腑功能失调的关系进行分析,发现各类症状中,仅对心瘾尚未提出当从何脏腑论治。因此以心瘾形成的核心机制“动机异常”为切入点,结合大量文献研究,采用类比法、演绎法对阿片类物质心瘾形成与脏腑失调的关系进行深入探讨。结果:阿片类物质心瘾形成是“肝主疏泄”、“肝司谋虑”、“肾藏志”等肝肾功能失调的结果。结论:阿片类物质心瘾作为一种情志疾病,其形成的核心证候基础为“肝失疏泄”,也与肾之阴阳不足相关。
理论研究二痰浊内阻与阿片类物质成瘾的关系
方法:结合文献研究,对“痰”的产生机制、致病特性进行探讨,并采用类比法、演绎法对“痰”这一病理产物与阿片类物质心瘾持续顽固存在的关系进行探讨。结果:“痰”是在疾病发展进程中形成的一种病理产物,同时又作为一种致病因素对疾病产生影响,阿片类物质心瘾持续顽固的特性与“痰”的致病特点极为吻合。结论:痰浊的形成是阿片类物质依赖发展到一定程度的结果,“痰”是心瘾持续顽固的主要病因。
以此为基础提出本研究的理论结论:阿片物质成瘾中各类急性戒断症状和稽延性戒断症状分别与不同脏腑的功能失调相关,其中阿片类物质心瘾形成核心相关证候为“肝失疏泄”,与肾阴阳两虚也密切相关;另外,当阿片类物质成瘾发展到一定阶段会导致痰浊内停,成为心瘾持续顽固的证候基础。在实验研究中,对心瘾形成相关证候进一步验证,并探讨的其病理机制。
研究二阿片类物质心瘾形成相关证候及神经生物学基础研究
实验研究一阿片类物质心瘾动物模型的优化和评价
方法:本研究在条件位置偏爱经典模型的基础上,结合本实验室的NODULE公司行为学研究装置建立了条件位置偏爱自动观察分析系统,根据非倾向性实验设计的原理采用非自然偏爱箱白箱为伴药箱,并在本实验室条件下,分别采用5mg/kg、10mg/kg和15mg/kg连续10天皮下注射吗啡的方法对大鼠进行条件位置训练50min,对照组大鼠仅注射生理盐水。训练结束后,进行条件位置偏爱测试15min。结果:条件位置偏爱自动观察分析系统对吗啡诱导的条件位置偏爱行为进行了实时记录和模式化分析,三种吗啡剂量训练50min均能使大鼠产生条件性位置偏爱,但相比之下,10mg/kg和15mg/kg的吗啡用量所产生的位置偏爱要更加明显,但15mg/kg的吗啡用量大鼠易激惹,且活动性差。结论:条件位置偏爱自动观察系统对吗啡诱导的条件位置偏爱行为进行实时记录和模式化分析,排除了非条件环境的干扰因素,具有精确、客观的优点,这在动物行为学观测中具有非常重要的意义。10mg/kg皮下注射为最佳吗啡诱导剂量,既能产生明显的条件位置偏爱效应,操作性也最强。在进一步的实验中,采用本实验心瘾模型的优化方案:非倾向性实验设计,皮下注射吗啡10mg/kg,训练时间为50min,连续造模10天,训练结束后进行测试15min,在自动观察系统中进行观察分析。
实验研究二以方测证探讨心瘾形成相关中医证候
方法:采用实验一的优化方案建立条件位置偏爱模型,结合所在课题组前期临床证候调查结果,将临床实践抗复吸有效方虎门合剂化裁为补肾方、疏肝方、化痰方和养心方,采用以方测证的方法,观察各个证型针对方对条件位置偏爱的改善作用,进而对理论结论中心瘾形成相关证候进行验证。结果:与心瘾模型组相比,补肾组和疏肝组大鼠在伴药箱中的停留时间显著下调(P＜0.05),化痰组在伴药箱内的停留时间虽有下调趋势,但无显著差异,而养心组的大鼠在伴药箱的停留时间无变化。结论:补肾方、疏肝方对吗啡诱导的条件位置偏爱行为有所改善,养心方无显著改善,通过行为学进一步验证了理论结论,肝失疏泄、肾阴阳两虚是阿片类物质心瘾形成的证候基础。而化痰方表现出对条件位置偏爱行为有所改善但无显著差异的原因可能与造模的时间、造模的方式所代表的疾病进程有一定关系,有待进一步研究。
实验研究三心瘾形成相关中医证候与Syp的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区Syp的阳性反应物、蛋白表达量和mRNA表达水平。结果:免疫组化结果显示在前额叶皮质和伏核中,Syp免疫阳性产物呈棕黄色,分布在胞浆中,各组阳性反应物无显著差异。Western blot结果显示,与对照组相比,伏核中模型组Syp蛋白表达显著升高(P＜0.05);前额叶皮质中Syp蛋白表达差异不具有显著性。与模型组相比,伏核中补肾组和疏肝组Syp蛋白表达显著下调(P＜0.05),而前额叶皮质中Syp蛋白表达无显著差异。其它组方无显著调节作用。Real time PCR结果显示,与对照组相比,伏核和前额叶皮质中模型组Syp的mRNA表达均无显著差异。与模型组相比,伏核和前额叶皮质中,补肾组Syp的mRNA表达均无显著差异,伏核中疏肝组Syp的mRNA表达显著下调(P＜0.05),前额叶皮质中疏肝组Syp的mRNA表达无显著差异。结论:在阿片类物质心瘾模型中,伏核中Syp的蛋白表达的上调与阿片类物质心瘾的形成相关。补肾方能显著下调Syp蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调,养心方和化痰方没有明显疗效。进一步验证了阿片类心瘾的形成在肝肾而不在心,也表明肝肾功能与高级中枢系统突触塑性密切相关,其失调的机制之一为伏核中与突触可塑性密切相关的Syp蛋白表达的异常,更深层次的机制有待进一步研究。
实验研究四心瘾形成相关中医证候与NMDA受体调节亚基的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区NMDA调节亚基NR2A、NR2B的阳性反应物、蛋白表达量和mRNA表达水平。结果:对NR2A,免疫组化和Western blot结果显示,在伏核和前额叶皮质中,模型组中NR2A免疫染色阳性神经元数及蛋白表达变化不显著,各个组方对NR2A的表达无显著调节作用。对于NR2B,免疫组化结果显示,与对照组相比,伏核和前额叶皮质中模型组NR2B阳性神经元数均显著上升(P＜0.05)。与模型组相比,伏核中补肾组NR2B阳性神经元数显著下调(P＜0.05),前额叶皮质中补肾组NR2B阳性神经元数无显著变化;与模型组相比,伏核和前额叶皮质中,疏肝组NR2B阳性神经元数显著下调(P＜0.05)。其他组方无明显的调节作用。Western blot结果显示,与对照组相比,伏核中模型组NR2B蛋白表达极显著升高(P＜0.01);前额叶皮质中NR2B蛋白表达显著升高(P＜0.05)。与模型组相比,补肾组和疏肝组伏核和前额叶皮质中NR2B蛋白表达均显著下调(P＜0.05),但与对照组相比,补肾组伏核中NR2B蛋白表达仍显著较高(P＜0.05)。其它组方无显著调节作用。Real time PCR结果显示,与对照组相比,伏核中模型组NR2B的mRNA表达极显著升高(P＜0.01),前额叶皮质mRNA表达也显著升高(P＜0.05)。与模型组相比,伏核和前额叶皮质中疏肝组NR2B的mRNA表达显著下调(P＜0.05)。其它组方无显著调节作用。结论:伏核和前额叶皮质中,NR2A调节亚基表达水平与阿片类物质心瘾的形成无显著相关,NR2B蛋白和基因水平的改变可能是阿片类物质心瘾形成的分子机制之一。在伏核和前额叶皮质中补肾方能显著下调NR2B蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调,再一次证明阿片类物质心瘾形成的主要病机是肝肾失调的同时,表明肝失疏泄的神经生物学本质与NR2B调节亚基在蛋白和基因水平的失调有关;肾阴阳不足的本质与NR2B蛋白表达水平的失调关系更为密切。
实验研究五心瘾形成相关中医证候与BDNF的关系
方法:实验二中各组大鼠条件位置偏爱行为学测试结束后,随机选取8只进行免疫组织化学研究,随机选取5只左侧半脑进行Western blot研究,右侧半脑进行real timePCR研究,检测伏核、前额叶皮质两个脑区BDNF的阳性反应物、蛋白表达量和mRNA表达水平。结果:免疫组化结果显示,与对照组相比,伏核中模型组BDNF阳性神经元数极显著升高(P＜0.01),前额叶皮质中模型组BDNF阳性神经元数也显著升高(P＜0.05)。与模型组相比,伏核和前额叶皮质中,补肾组和疏肝组BDNF阳性神经元数均显著下调(P＜0.05),但与对照组比较,疏肝组伏核中BDNF神经元仍显著较高(P＜0.05)。其他组方无显著调节作用。Western blot结果显示,与对照组相比,伏核和前额叶皮质中,模型组BDNF蛋白表达显著升高(P＜0.01)。与模型组相比,伏核补肾组和疏肝组BDNF蛋白表达显著下调(P＜0.05),而前额叶皮质中BDNF蛋白表达极显著下调(P＜0.01)。Real time PCR结果显示,与对照组相比,伏核和前额叶皮质中模型组BDNF的mRNA表达均极显著升高(P＜0.01)。与模型组相比,伏核和前额叶皮质中疏肝组BDNF的mRNA表达显著下调(P＜0.05),但与对照组比较,前额叶皮质中BDNF mRNA表达仍显著升高(P＜0.05)。结论:伏核和前额叶皮质中,BDNF蛋白表达和mRNA表达的升高均与阿片类物质心瘾的形成相关,表明BDNF蛋白和基因水平的改变可能是阿片类物质心瘾形成的分子机制之一。对于BDNF蛋白和基因水平的调节作用,在伏核和前额叶皮质中补。肾方能显著下调其蛋白表达水平,而疏肝方则使其蛋白表达水平和mRNA表达水平均有显著下调。表明“肝失疏泄”的神经生物学本质与BDNF在蛋白和基因水平的失调有关;肾阴阳不足的本质仅与BDNF蛋白表达水平的失调关系更为密切。结合对NR2B及Syp的研究,认为阿片类物质心瘾的中医病机主要责之于肝肾,因此本研究结果进一步扩展了肝肾的本质在现代神经生物学中的外延,在中枢神经系统内,肝失疏泄与动机系统的突触可塑性改变相关,本研究可见伏核和前额叶皮质中可塑性相关蛋白在基因和蛋白水平的失调;而肾虚则主要与前额叶皮质和伏核中突触可塑性相关指标在蛋白水平的失调有关。
本研究在经典条件位置偏爱模型的基础上,利用本实验室新引进的NODULE公司行为学研究装置建立自动化条件位置偏爱观察分析系统,从而减少了非条件环境因素对吗啡相关条件线索的干扰,对不同剂量吗啡引起的条件位置偏爱效应进行比较,从而结合现代行为学手段,使阿片类物质心瘾模型进一步优化。采用演绎法、类比法及引证法等对阿片类物质心瘾相关的证候进行理论研究,在此基础上,将临床抗戒断有效方虎门合剂化裁为四个证型针对方,进一步采用以方测证的方法进行了行为学验证,对阿片类物质心瘾形成相关证候提出:心瘾形成的主要证候基础是“肝失疏泄”,同时肾之阴阳不足对心瘾的形成也有重要影响。对阿片类物质心瘾的神经生物学本质进行了探讨,结合伏核、前额叶皮质的突触可塑性在阿片类物质心瘾与异常用药动机形成的关系,以及Syp、NR2B亚基和BDNF三个蛋白与突触可塑性、心瘾的关系,本研究认为阿片类物质心瘾的形成与伏核和前额叶皮质中NR2B和BDNF的基因和蛋白水平的升高,伏核中Syp的蛋白水平升高相关。在病证结合的研究思路指导下,对阿片类物质心瘾相关证候的神经生物学本质进行了探讨,本研究认为心瘾形成相关肝失疏泄证的现代生物学本质为Syp、NR2B和BDNF在蛋白和基因水平的失调引起的伏核和前额叶皮质的突触可塑性变化;而肾阴阳不足的本质则在于以上三个指标在蛋白水平失调引起的上述脑区突触可塑性变化。通过上述研究,本研究对肝肾本质有更进一步的认识,在既往研究将“肝肾同源于精血”推进到“肝肾同源于脑”的基础上,又进一步扩展到“肝肾同源于动机回路”。
Along with the exogenous opioid abuse becomes the public disruption in the world,in China the abusers is increasing sharply.Drug addiction is a chronic and recurrent encephalopathy,which is difficult to solve in modern medicine.Over the last 20 years,due to the general research in the pathogenesis and the therapeutics to drug abuse,detoxification can be cured completely,and the acute withdrawal syndrome,protracted physical dependence can be treated directly too.But the obsessive drug-craving,the main reason for relapse,is the hang-up to cure the drug addiction radically.
The treatment based on syndrome differentiation is the characteristic of the Chinese medicine.Drug abuse is treated for hundreds of years by Chinese medicine,but the cognitions about the etiopathogenisis and pathogenesis are only confined to personal experiences,which is the shackle to treat craving objectively and systematically.
To cure drug-craving in modern medicine and Chinese medicine,the study on syndrome of drug craving systematically and objectively is necessary.The research explores the syndrome differentiation of drug craving in both theory and experiment,which will afford objective evidence and systematical theory to guide the treatment of drug craving in clinic.
The thesis contains theoretical and the experimental study:in the theoretical part, deduction,analogism and the citation were used to elicit the hypothesis on the pathogenesis and syndrome of drug-craving;in the experimental part,the method to detect the syndrome by formula was used to certify the hypothesis.First,according to the research of syndromes for years clinically,the effective formula to prevent relapse,named "hu men he ji" was divided into four sub-formulas aiming at different syndromes,called "invigorating the kidney formula" "dispersing the depressed liver-energy formula" "dissipating phlegm formula" and "supporting heart formula".And then we assessed the syndromes by detecting the effect of the above sub-formulas to conditioned place preference induced by morphine and analyzed pathogenesis of related syndromes,for the nucleus accumbens(NAc) and Cortex of frontal lobe(PFC) are the crucial encephalic regions in drug addiction,and the synaptic plasticity is the fundamental pathogenesis of drug-craving,the analysis focused on the relation between the drug-craving and the synaptic plasticity in NAc and PFC.
PartⅠThe theoretical study on the syndromes of drug-craving Theoretical study one:the relation between entrails and drug addiction
Method:By literature study,the relation between all kinds of withdrawal symptoms and functional disorder of entrails was analyzed by induction,and the related organs to drug-craving was unkown,together with the core mechanism of drug-craving,analogism,deduction,and citation were used to analyze the relation between the "liver controlling dispersion" and the formation of drug-craving.And the relation between "liver managing deliberation" "kidney controlling aspiration" and the formation of drug-craving is analyzed by deduction,and citation too.Result:The formation of drug-craving is the result of functional disorder of "liver controlling dispersion" "liver managing deliberation" and "kidney controlling aspiration".Conclusion:Drug-craving is an emotional disease,the core syndrome of which is "liver failing to control dispersion",and other related syndromes are "Yin and Yang deficiency of kidney".
Theoretical study two:Phlegm should be responsible for persistence of drug-craving
Method:By literature study,the production and morbigenous characteristic were analyzed,analogism and deduction were used to analyze the relation between the pathogen of phlegm and the persistence of drug-craving.Result:Phlegm is a patho-product of diseases, which influences the disease as a pathogen too.The persistence of drug-craving coincides with the morbigenous characteristics of phlegm.Conclusion:The phlegm,which resulted from drug addiction,is the main reason for the persistence of drug-craving.
The conclusion of theoretical part:Different withdrawal symptoms are related to different entrails,and the core syndrome of fonnation of drug-craving is "liver failing to control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney". The phlegm,which resulted from drug addiction,is the main reason for the persistence of drug-craving.In experimental study,the theoretical conclusion will be verified further.
PartⅡThe experimental study on the syndromes of drug-craving Experiment one:Optimization and evaluation of the conditioned place preference
Method:Based on the classical conditioned place preference(CPP),automatic test system of CPP was set up to make use of the behavioral equipment and software from NODULE corporation.According to unbiased design,white compartment was designed as the morphine-paired compartment.Morphine(5mg/kg,10mg/kg,or 15mg/kg,i.p.) was separately administrated in white compartment and saline on the other side.In control group,0.9% sodium chloride(10mg/kg,i.p.) was administrated on both sides.Conditioning consisted of 50-min sessions,and testing was for 15min.Result:Real-time recording and hipping analysis to CPP came true in the automatic test system.CPP could be induced successfully by morphine of the above three doses.CPP induced by morphine of 10mg/kg and 15mg/kg were more obvious,but rats injected by morphine of 15mg/kg showed irritability and low reactiveness,so the 10mg/kg was optimized dose for CPP in the study.Conclusion:The automatic test system of CPP are more accurate and objective,for it can make real-time recording and hipping analysis to behavior,and eliminate the disturbance of unconditioned clues.10mg/kg is the optimized dose to induce the CPP by i.p..The above optimized scheme will be used in further study.
Experiment two:the relation between the malfunction of liver and kidney and the formation for drug craving
Method:The optimized design by experiment one was used to set up the CPP.Method to detect the syndrome by formula were used to certify the theoretical study.According to clinical study on syndromes of opiod dependence for years,the effective formula to prevent relapse,named "hu men he ji" were divided into four sub-formulas aiming at different syndromes,called "invigorating the kidney formula" "dispersing the depressed liver-energy formula" "dissipating phlegm formula" and "supporting heart formula".And then modulation of the four formulas to rewarding effect in CPP induced by morphine was detected.Result: The time staying in white compartment of model group was significantly longer than that of control(P＜0.01).Compared to model group,the time staying in white compartment of both "invigorating the kidney group" and "dispersing the depressed liver-energy group" was significantly reduced(P＜0.01).And the mean time staying in white compartment of dissipating phlegm group reduced too,but there was no significant difference to the model group,and the supporting heart formula had no effect.Conclusion:"invigorating the kidney formula" and "dispersing the depressed liver-energy formula" can alter the CPP induced by morphine,together with the previous study,"liver failing to control dispersion" is considered as the core syndrome of the formation of drug-craving,and other related syndrome is the "Yin and Yang deficiency of kidney".
Experiment three:The relation between synaptophysin and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:In immunohistochemistry,in NAc and PFC the synaptophysin's positive products were buffer granules,which distributed in cytoplasm,and had no significant difference in each group.In western blot,compared to control group,the protein of synaptophysin of model group increased in NAc(P＜0.05),but not in PFC.Compared to model group,in NAc the protein of synaptophysin of the invigorating kidney group and the invigorating liver group decreased significantly(P<0.05), and had no chang in PFC.No significant differences were found in other groups.In real time PCR,there was no significant difference between control group and model group.But compared to the model group,the expression of synaptophysin's mRNA were down-regulated in invigorating liver group in NAc(P<0.05),and had no difference in other encephalic region. Conclusion:In the study,synaptophysin,related to synaptic plasticity,is up-regulated in NAc, so it probably is a main reason for drug-craving,but the further pathology still need be studied. Invigorating kidney formula can down-regulate the protein of synaptophysin,and the invigorating liver formal can down regulate both the protein and the gene expression,and other formulas have no effect.The above proves the theoretical study that the kidney and liver, but not heart,should be responsible for formation of drug-craving,and the dysfunction of kidney and liver is correlated to the synaptic plasticity due to the increase of the synaptophysin in the NAc.
Experiment four:The relation between regulatory subunit of NMDA receptor and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:NR2A and NR2B regulatory subunit were studied.In immunohistochemistry,in NAc and PFC,NR2A's positive products had no significant difference in each group.Compared to control group,NR2B's positive products increased in both NAc and PFC(P<0.05),and compared to model group, invigorating kidney formula down-regulated NR2B's positive products in NAc(P<0.05), invigorating liver group down-regulated NR2B's positive products in both NAc and PFC(P<0.05),other formulas didn't have effect.In Western blot,compared to control group, the protein of NR2B increased significantly in NAc(P<0.01),and increased in PFC too(P<0.05).Compared to model group,invigorating kidney and invigorating liver formulas could down-regulate the protein of NR2B in both NAc and PFC(P<0.05),but still higher than the control group in NAc in invigorating kidney group(P<0.05).In real time PCR,compared to the control group,the expression of mRNA of NR2B increased significantly in NAc(P<0.01),and increased in PFC too(P<0.05).Compared to model group,invigorating liver formula could down regulate expression of mRNA in both NAc and PFC(P<0.05).Conclusion:in NAc and PFC,the change of NR2B in protein and gene level is related to the formation of drug-craving,not NR2A.In NAc and PFC,invigorating kidney formula can down-regulate the protein of NR2B,and invigorating liver formula can down-regulate both protein and gene of NR2B,Other formulas had no effect.The experiment proves that the kidney and liver should be responsible for drug-craving,but not heart,which means the pathology of drug-craving is the dysfunction of kidney and liver.The essence of "liver failing to control dispersion" is the up-regulation of NR2B in both protein and gene level,and "Yin and Yang deficiency of kidney" is due to the up-regulation of NR2B in protein level.
Experiment five:The relation between BDNF and the syndromes in formation of drug-craving
Method:After behavioral test of CPP in experiment two,in each group 8 rats were randomly chosen to be detected by the immunohistochemistry,and 5 rats were randomly chosen to be taken out the NAc and PFC,the left of which were detected by western blot and the right of which were detected by real time PCR.Result:In immunohistochemistry, compared to the control group,in NAc the reactive products of BDNF increased significantly in model group(P＜0.01),and in PFC the products increased too(P＜0.05).Compared to model group,in both NAc and PFC,invigorating kidney and invigorating liver formulas could down-regulate the reactive products(P＜0.05),but the products of invigorating liver group were still higher than the control group(P＜0.05).Other formulas had no effect.In western blot, compared to the control group,in NAc and PFC,the protein of BDNF increased significantly(P＜0.01).And compared to model group,in NAc invigorating kidney and invigorating liver groups down-regulated the protein of BDNF(P＜0.05),and in PFC down-regulated the protein remarkably(P＜0.01).In real time PCR,compared to the control group,in model group the gene expression of BDNF increased significantly(P＜0.01). Compared to model group,in NAc and PFC,invigorating liver formula could down-regulate the gene expression of BDNF(P＜0.05),but in PFC the gene expression of BDNF was still higher than control group(P＜0.05).Conclusion:In NAc and PFC,the increase of protein and gene of BDFN is related to the formation of drug-craving,which represents dysfunction of BDNF is probably the main reason of drug-craving.And in NAc and PFC,invigorating kidney formula only can down-regulate the protein of BDNF,but invigorating liver formula can regulate in both protein and gene level.Along with the experiment about synaptophysin and NMDA receptors,the research verify that the core syndrome of the formation of drug-craving is "liver failing to control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney",whose neurobiology essence is the synaptic plasticity due to dysfunction of related proteins like synaptophysin,NR2B and BDNF in PFC and NAc.
The research makes breakthrough in five sides:first,based on the classical CPP, automatic test system of CPP is set up to make use of the behavioral equipment and software from NODULE corporation,which are more accurate and objective,for it can make real-time recording and hipping analysis to behavior,and eliminate the disturbance of unconditioned clues.Second,provide theoretical conclusion to syndromes of drug-craving by deduction, citation and analogism,and then use formulas to verify that the core syndrome of the formation of drug-craving is "liver failing to Control dispersion",and other related syndrome is the "Yin and Yang deficiency of kidney".Third,the neurobiology essence of drug-craving is considered as the increase of NR2B and BDNF in both protein and gene level in PFC and NAc,and also related to increase of synaptophysin in protein level only in NAc.Four,the neurobiology essence of "liver failing to control dispersion" in formation of drug-craving is the synaptic plasticity due to dysfunction of related proteins such as synaptophysin,NR2B and BDNF in PFC and NAc in both protein and gene level,and "Yin and Yang deficiency of kidney" due to the dysfunction of the above in protein level.And above that,the research expand the essence of the kidney and liver that the two ZANG-organs are related to motive circuit in nerve center.
引文
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