脑立体定向手术用于戒毒治疗的动物实验和临床研究
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摘要
目的：
本研究旨在探讨应用定向手术毁损与阿片类药物产生心理(精神)依赖密切相关的脑内关键核团，阻断中脑-边缘多巴胺系统环路，缓解、消除药物的心理(精神)依赖，控制、降低脱毒后的复吸率，从而达到彻底戒除毒瘾，为临床戒毒提供一种新颖的、全面彻底的、安全有效的新方法。
方法：
本研究包括动物实验和临床研究两部分。
1．动物实验：
以大鼠为实验动物，以条件性地点偏爱实验为观察方法，比较毁损伏隔核、腹侧苍白球对动物觅药行为的作用，有无并发症发生，筛选出更适合应用于临床戒毒治疗的脑内毁损靶点。
(1)制作条件性地点偏爱实验箱，A侧为注射吗啡侧；
(2)40只大鼠随机平分为伏隔核毁损组和腹侧苍白球毁损组，每组又分为成瘾组和对照组；
(3)按逐日递增原则，在实验箱A侧向大鼠腹腔注射盐酸吗啡，通过戒断症状评分标准进行行为学评估，确定大鼠成瘾以及对实验箱A侧的偏爱(观察记录15min，900s大鼠在A、B两侧停留的平均时间)；
第四军二大学博士学位论文
N）定向手术毁损伏隔核、腹侧苍白球；
6）术后再次行条件性地点偏爱实验，记录、比较术前、
术后大鼠在实验箱A侧停留的平均时间，并与对照组（假
手术组）比较，观察手术对大鼠觅药行为的改变作用，
有无副作用及并发症发生；
L 临床研究：
根据动物实验的结果，在查阅文献、咨询专家、走访同
行、社会调查、学科论证的基础上，临床收治24例吸毒患
者行双侧伏隔核毁损术。
门）制定手术适应症标准：
吸毒史三年以上；
药物戒毒3次以上，脱毒后3周内发生复吸；
患者、家属自愿要求；
无手术禁忌。
u）制定疗效标准：
优：术后半年以上无复吸意念及行为；
良：术后半年内偶有复吸意念及行为，但较术前明显
减轻：
差：术后半年内发生复吸，毒癌发作程度基本同术前。
臼）规范治疗程序：
药物脱毒（依赖性药物，非依赖性药物）；
尿检、纳络酮催瘤试验结果阴性；
作者 王学廉 第5页2002A5．07
第四军巴大学博士学位论文
手术：采用CRW立体定向仪，Philip螺旋CT薄层扫
描（层厚 3mm，层距 ZnunX 伏隔核（accUmbens
nucleus）坐标：参照 SchaltembrandEailey人脑图谱，
ACqC线下 8－10nun，撇原点（MP）前侣－22nun，中
线旁开 41 onun，以伏隔核的核心部＊ore）做为原
始靶点。刺激频率及阈值：100HZ，6七；RadioniC
射频治疗仪；射频电极：1．smm；毁损温度85℃，时
间60s，每侧间隔3－4mm各毁损两个针道，每个针道
间隔1共毁损6个层面。
N）制定手术疗效及安全性观察评价指标：
尿检；
纳络酮催瘤实验；
血、尿、唾液、毛发中吗啡含量检测；
药物依赖诊断量表u＊IDoD）：
心理学调查量表：
艾森克人格问卷oPQ）。
明尼苏达多相人格调查表（MNQI）：
卡特尔十六种个性因素测查表门6N）：
药物心理依赖调查量表（自编人
（5）118th：
不定期随机抽查；
随访形式：家庭访问（面对面），门诊预约（面对面），
电话，邮寄填写随访调查表；
作者 王学廉 第6页22265．07
第四军区大学博士学位论文
随访期 0．5—22个月，平均随访期 13个月。
结果：
1．动物实验
门）在毁损伏隔核组中，经统计学分析，术前成瘤组大鼠
在A、B两侧各停留的平均时间与术前对照组大鼠在A、B两
侧各停留的平均时间相比，P＜0刀1，差异显著，有统计学意义，
表明术前成癌组大鼠对A侧有?
Objective:
Opiate drug dependence is a very serious medical and social problem.Drug dependence includes two aspects:physical dependence and psychic dependence/Though there has been a much progress of neuroscience in studying drug dependence and effective measures in controlling abstinence syndrome for many years,high relapse rate after detoxification due to intractable psychic dependence is still universally acknowledged as a difficult problem.At present,because of uncontrolling psychic dependence,treating drug dependence clinically is in a situation of detoxificating easily but de-addict difficultly.Correlation between psychological dependence and nerve nuclus <. neuro-circuu\ neuro-transmitter has been the focus of much recent investigation.Plenty of animal experiment results confirmed that there is an intimate relation between psychological dependence and mesocorticolimbic dopamine system.Both nucleus accumbens and ventral pallidum is the most important nuclus in the mesocorticolimbic dopamine system which play a very crucial role in drug-induced psychological dependence.Lesions made by surgical or chemical method in nucleus accumbens or ventral pallidum can change animals' drug-seeking behavior.But at present,making a lesion in nerve nuclus by stereotactic surgery to treat drug-induced psychological dependence is much more limited to animal experiments.No reports of using stereotactic surgery to deal with drug abstinence in human beings be recorded or published.
The objective of this study is to explore making a lesion in nerve nuclus which have intimate relation with drug-induced psychological dependence by stereotactic surgery,blocking mesocorticolimbic dopamine circuit, alleviating or getting rid of craving for drugs,lowering relapse rate after detoxification and developing a new,complete,safe and effectiveness therapy of drug abstinence.
Methods:
The study includes two parts:animal experiment and clinical study. lAnimal experiment:
40 male SD rats were used as animal models.A case of conditioned place preference.was made and A side was paired with injection morphine.Electrolytic lesions of the nucleus accumbens and ventral pallidum was done separately in 20 rats and changes of drug-seeking behavior was observed by conditioned place preference.Each group of rats again divided into morphine dependence group and controlling group.Recording and comparing mean time of rat staying in A side pre-operation and post-operation to screen out which nucleus is safer and more effectively lesioned in human beings by stereotactic surgery .Side effects and complications were also observed.
2.Clinical study:
On the basis of animal experiment,we did 24 cases of stereotactic surgery making a lesion in nucleus accumbens bilaterally to treat opiate drug dependence. Indications, criterion of therapeutical effect,treatment process, therapeutical and safe evaluation index of the surgery were formulated particularly.
(1) Indications criterion:
drug-taking history is more than 3 years, detoxification is more than 3 times,
relapse occurred within 3 weeks after each time of detoxification, patients underwent the operation of their own free will, no contraindications.
(2) Criterion of therapeutical effect:
excellent: relapse ideas and behavior not occurred over half of a year after surgery;
good: relapse ideas and behavior occurred occasionally within half of a year after surgery, but the withdrawal symptoms was obviously alleviated than that of pre-operation;
poor: relapse occurred within half a year after surgery and the withdrawal symptoms were as well as that of pre-operation;
(3) Treatment process:
(D patients should be treated by medication for detoxification; ?results of drug urinalysis and naloxone test was negative; (? the operation could be done.
(4) Therapeutical and safe evaluation index of the surgery:
(1) drug urinalysis;
(2) naloxone test;
(3) drug testing in blood,urine,saliva and hair,
(4) schedule of clinical interview for diagnosis of drug dep
本研究旨在探讨应用定向手术毁损与阿片类药物产生心理(精神)依赖密切相关的脑内关键核团，阻断中脑-边缘多巴胺系统环路，缓解、消除药物的心理(精神)依赖，控制、降低脱毒后的复吸率，从而达到彻底戒除毒瘾，为临床戒毒提供一种新颖的、全面彻底的、安全有效的新方法。
方法：
本研究包括动物实验和临床研究两部分。
1．动物实验：
以大鼠为实验动物，以条件性地点偏爱实验为观察方法，比较毁损伏隔核、腹侧苍白球对动物觅药行为的作用，有无并发症发生，筛选出更适合应用于临床戒毒治疗的脑内毁损靶点。
(1)制作条件性地点偏爱实验箱，A侧为注射吗啡侧；
(2)40只大鼠随机平分为伏隔核毁损组和腹侧苍白球毁损组，每组又分为成瘾组和对照组；
(3)按逐日递增原则，在实验箱A侧向大鼠腹腔注射盐酸吗啡，通过戒断症状评分标准进行行为学评估，确定大鼠成瘾以及对实验箱A侧的偏爱(观察记录15min，900s大鼠在A、B两侧停留的平均时间)；
第四军二大学博士学位论文
N）定向手术毁损伏隔核、腹侧苍白球；
6）术后再次行条件性地点偏爱实验，记录、比较术前、
术后大鼠在实验箱A侧停留的平均时间，并与对照组（假
手术组）比较，观察手术对大鼠觅药行为的改变作用，
有无副作用及并发症发生；
L 临床研究：
根据动物实验的结果，在查阅文献、咨询专家、走访同
行、社会调查、学科论证的基础上，临床收治24例吸毒患
者行双侧伏隔核毁损术。
门）制定手术适应症标准：
吸毒史三年以上；
药物戒毒3次以上，脱毒后3周内发生复吸；
患者、家属自愿要求；
无手术禁忌。
u）制定疗效标准：
优：术后半年以上无复吸意念及行为；
良：术后半年内偶有复吸意念及行为，但较术前明显
减轻：
差：术后半年内发生复吸，毒癌发作程度基本同术前。
臼）规范治疗程序：
药物脱毒（依赖性药物，非依赖性药物）；
尿检、纳络酮催瘤试验结果阴性；
作者 王学廉 第5页2002A5．07
第四军巴大学博士学位论文
手术：采用CRW立体定向仪，Philip螺旋CT薄层扫
描（层厚 3mm，层距 ZnunX 伏隔核（accUmbens
nucleus）坐标：参照 SchaltembrandEailey人脑图谱，
ACqC线下 8－10nun，撇原点（MP）前侣－22nun，中
线旁开 41 onun，以伏隔核的核心部＊ore）做为原
始靶点。刺激频率及阈值：100HZ，6七；RadioniC
射频治疗仪；射频电极：1．smm；毁损温度85℃，时
间60s，每侧间隔3－4mm各毁损两个针道，每个针道
间隔1共毁损6个层面。
N）制定手术疗效及安全性观察评价指标：
尿检；
纳络酮催瘤实验；
血、尿、唾液、毛发中吗啡含量检测；
药物依赖诊断量表u＊IDoD）：
心理学调查量表：
艾森克人格问卷oPQ）。
明尼苏达多相人格调查表（MNQI）：
卡特尔十六种个性因素测查表门6N）：
药物心理依赖调查量表（自编人
（5）118th：
不定期随机抽查；
随访形式：家庭访问（面对面），门诊预约（面对面），
电话，邮寄填写随访调查表；
作者 王学廉 第6页22265．07
第四军区大学博士学位论文
随访期 0．5—22个月，平均随访期 13个月。
结果：
1．动物实验
门）在毁损伏隔核组中，经统计学分析，术前成瘤组大鼠
在A、B两侧各停留的平均时间与术前对照组大鼠在A、B两
侧各停留的平均时间相比，P＜0刀1，差异显著，有统计学意义，
表明术前成癌组大鼠对A侧有?
Objective:
Opiate drug dependence is a very serious medical and social problem.Drug dependence includes two aspects:physical dependence and psychic dependence/Though there has been a much progress of neuroscience in studying drug dependence and effective measures in controlling abstinence syndrome for many years,high relapse rate after detoxification due to intractable psychic dependence is still universally acknowledged as a difficult problem.At present,because of uncontrolling psychic dependence,treating drug dependence clinically is in a situation of detoxificating easily but de-addict difficultly.Correlation between psychological dependence and nerve nuclus <. neuro-circuu\ neuro-transmitter has been the focus of much recent investigation.Plenty of animal experiment results confirmed that there is an intimate relation between psychological dependence and mesocorticolimbic dopamine system.Both nucleus accumbens and ventral pallidum is the most important nuclus in the mesocorticolimbic dopamine system which play a very crucial role in drug-induced psychological dependence.Lesions made by surgical or chemical method in nucleus accumbens or ventral pallidum can change animals' drug-seeking behavior.But at present,making a lesion in nerve nuclus by stereotactic surgery to treat drug-induced psychological dependence is much more limited to animal experiments.No reports of using stereotactic surgery to deal with drug abstinence in human beings be recorded or published.
The objective of this study is to explore making a lesion in nerve nuclus which have intimate relation with drug-induced psychological dependence by stereotactic surgery,blocking mesocorticolimbic dopamine circuit, alleviating or getting rid of craving for drugs,lowering relapse rate after detoxification and developing a new,complete,safe and effectiveness therapy of drug abstinence.
Methods:
The study includes two parts:animal experiment and clinical study. lAnimal experiment:
40 male SD rats were used as animal models.A case of conditioned place preference.was made and A side was paired with injection morphine.Electrolytic lesions of the nucleus accumbens and ventral pallidum was done separately in 20 rats and changes of drug-seeking behavior was observed by conditioned place preference.Each group of rats again divided into morphine dependence group and controlling group.Recording and comparing mean time of rat staying in A side pre-operation and post-operation to screen out which nucleus is safer and more effectively lesioned in human beings by stereotactic surgery .Side effects and complications were also observed.
2.Clinical study:
On the basis of animal experiment,we did 24 cases of stereotactic surgery making a lesion in nucleus accumbens bilaterally to treat opiate drug dependence. Indications, criterion of therapeutical effect,treatment process, therapeutical and safe evaluation index of the surgery were formulated particularly.
(1) Indications criterion:
drug-taking history is more than 3 years, detoxification is more than 3 times,
relapse occurred within 3 weeks after each time of detoxification, patients underwent the operation of their own free will, no contraindications.
(2) Criterion of therapeutical effect:
excellent: relapse ideas and behavior not occurred over half of a year after surgery;
good: relapse ideas and behavior occurred occasionally within half of a year after surgery, but the withdrawal symptoms was obviously alleviated than that of pre-operation;
poor: relapse occurred within half a year after surgery and the withdrawal symptoms were as well as that of pre-operation;
(3) Treatment process:
(D patients should be treated by medication for detoxification; ?results of drug urinalysis and naloxone test was negative; (? the operation could be done.
(4) Therapeutical and safe evaluation index of the surgery:
(1) drug urinalysis;
(2) naloxone test;
(3) drug testing in blood,urine,saliva and hair,
(4) schedule of clinical interview for diagnosis of drug dep
引文
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49. Alderson HL,Parkinsobn JA,Robbins TW, Everitt BJ.The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats.Psychopharmacology (Berl), 2001, Feb;153(4):455-63
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60．韩珍．盐酸纳络酮的药理作用与临床应用．中国药物依赖性杂志．2001；10(4)：249～250
61．刘忠华，张开镐．基因敲除小鼠在药物依赖性研究中的应用．中国药物依赖性杂志．2001；10(2)：82～85
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63．李祯英．海洛因依赖者脱毒后复吸的原因及防复吸措施．中国药物依赖性杂志．2001；10(4)：304
64．罗祥华，袁丁．海洛因依赖者戒毒前后的个性比较．中国药物依赖性杂志．1999；8(3)：213～214
65．陈焕济，戎铁斌，苏木金．减少自愿戒毒病人出院后复吸的几项有效措施．中国药物滥用防治杂志．2000；29(6)：22～23
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68．黄航，吴小云，林木添，等．海洛因依赖者心理健康状况调查．中国临床心理学杂志．2001；9(1)：58～59
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46．彭罗民，傅桂兰，王军霞，等．血液净化治疗海洛因成瘾临床观察(附52例71例次报告)．中国药物滥用防治杂志 2000，1：26～28
47．李冰，张金伟，刘灿虎，等．伽玛刀联合靶点戒毒5例临床初步报告．哈尔滨医科大学学报，2000，1：73
48. Hutcheson DI,Parkinson JA,Robbins TW, Everitt BJ.The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement. Psychopharmacology(Berl), 2001, Feb;153(4):464-72
49. Alderson HL,Parkinsobn JA,Robbins TW, Everitt BJ.The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats.Psychopharmacology (Berl), 2001, Feb;153(4):455-63
50．师建国主编．成瘾医学．第1版．北京：科学出版社，2002；1-86．
51．纪家涛，王新华，由振东。吗啡依赖大鼠模型的建立。第二军医大学学报。1997；18(2)：81～82
52．刘宗惠主编．外科特种兵神奇伽马刀．第1版．深圳：海天出版社，2000，106～112
53．郑希耕，隋南．吗啡作用的中枢机制及相关的基因调控．中国神经科学杂志．2001，17(4)：343～346
54．张开镐．药物依赖性的动物实验方法(一)．中国药物依赖性杂志．1999；8(1)：23～26
55．郑继旺．有关药物依赖性几个基本概念的说明．中国药物滥用防治杂志．1999；18(1)：47～48
56. S.Tiffany Cunningham.Ann e. Kellry. Opiate infusion into nucleus accumbens:contrasting effects on motor activity and responding for conditioned reward. Brain Research. 1992;588:104～114
57．王玢，罗非，韩济生．阿片成瘾机制研究进展及治疗展望．生理科学进展．1998；29(4)：295～300
58．王玢，罗非，韩济生．参与阿片身体依赖的核团及受体后过程．中国神经科学杂志．1999；15(1)：63～68
59．陈志，冯华．吗啡依赖大鼠模型的戒断行为学比较．中国行为医学科学．2001；10(1)：11～12
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62．殷彬，臧德馨．阿片类药物对神经递质的影响．国外医学精神病学分册．1997；24(2)：85～88
63．李祯英．海洛因依赖者脱毒后复吸的原因及防复吸措施．中国药物依赖性杂志．2001；10(4)：304
64．罗祥华，袁丁．海洛因依赖者戒毒前后的个性比较．中国药物依赖性杂志．1999；8(3)：213～214
65．陈焕济，戎铁斌，苏木金．减少自愿戒毒病人出院后复吸的几项有效措施．中国药物滥用防治杂志．2000；29(6)：22～23
66．周文华，张富强，杨国栋．复吸的神经网络、神经元适应和复吸模型．中国药物依赖性杂志．2001；10(1)：6～8
67．刘绍忠，张建军，刘金凤．海洛因依赖者复吸心理分析．中国药物滥用防治杂志．2000；27(4)：21～24
68．黄航，吴小云，林木添，等．海洛因依赖者心理健康状况调查．中国临床心理学杂志．2001；9(1)：58～59
69. Parkinson JA, Willoughby PJ,Robbins TW. et al. Disconnection of the anterior cingulated cortex and nucleus accumbens core impairs Pavlovian approach behavior:further evidence for limbic cortical- ventral striatopallidal systems.Psychopharmacology (Berl) 2001;153(4):455～63
70. Hatip-Al-khafi I,Bolukbasi F, Mishima K, et al. Role of dopaminergic system in core part of nucleus accumbens in hyperlocomotion and rearing induced by MK-801 in rats:a behavioral and in vivo microdialysis study. Jpn J P HARMACOL 2001 Dec;87(4):277～87
71．魏孝琴，袁奇，邵云，等．伏隔核毁损对大鼠吗啡成瘾与戒断的影响及行为变化的研究．中国医科大学学报．1998；27(3)：263～266
72. Billy Chieng. MacDonald J.Christie. Local Opioid Withdrawal in Rats Single Periaqueductal Gray Neurons In Vitro. The Journal of Neuroscience. 1996; 16(22):7128～7136
73．谌红献，张瑞岭，郝伟．东莨菪碱对SD大鼠吗啡位置偏爱的影响．中国行为医学科学．2001；10(4)：289～290
74. Ellen M.Unterwald. Ann Tempel. George F. Koob et al. Characterization of opioid receptors in rat nucleus accumbens following mesolimbic dopaminergic lesions. Brain Research; 1989(505): 111～118
75. Kurt Rasmussen. George K.Aghajanian.withdrawal-induced activation of locus coeruleus neurons in opiate-dependent
rats: attenuation by lesions of the nucleus paragigantocellularis.Brain Reaearch;1989(505) :346-350
76． D.S.ZAHM.LENNART HEMER. Specificity in the efferent projections of the nucleus accumbens in the rat:comparison of the rostral pole projection patterns with those of the core and shell.The Journal og comparative neurology: 1993(327) :220-232