摘要
[目的]
当前,MDMA在全世界泛滥流行,是法医学和毒理学研究的热点之一。目前有关MDMA的研究主要局限于24h以上的毒性作用机制,而人们对24h以内的MDMA如何影响人体知之甚少。由于服用MDMA最短可在几分钟内起效,对人体中枢神经系统产生影响,因此对24h内神经系统MDMA的作用机制的研究非常必要。本课题利用多种方法和技术,从氧化应激、细胞凋亡和内质网Ca2+通道等方面对MDMA染毒大鼠24h内脑组织进行研究,希望能进一步阐述MDMA中毒的特点及对机体的影响,为完善MDMA法医毒理学作用机制奠定理论基础。
[方法]
实验1:
1.建立腹腔注射MDMA(20mg/kg)成年SD大鼠染毒模型,实验组27只,对照组5只。拟将实验组按染毒后1h、12h和24h分组处死,每组9只。在处死1h组实验动物后,2-6h内有6只大鼠发生死亡,故将其分为自发死亡组,剩余12只实验动物随机分为12h处死组和24h处死组,每组6只,取脑组织备用;
2.用高效液相色谱法测定不同时间段各组脑组织内5-HT和DA含量;
3.用硫代巴比妥酸法和羟胺法分别测定不同组间SOD、MDA的活性;
实验2:
1.染毒步骤同实验1,动物及分组为实验1中的对照组、1h组、12h组和24h组。
2.用HE、TUNNEL及免疫组化的方法染各组脑组织切片,并用Western Blot方法测定各组Bcl-2、Bax及Caspase-3的含量;
实验3:
1.染毒及分组同实验2
2.用RT-PCR和免疫组化的方法测定Ryr2和SERCA2的表达情况。
[结果]
实验1:
1.染毒大鼠有明显的毒性反应,染毒后自发死亡的大鼠均在染毒6h内发生,死亡率为22.22%。
2.处死组与自发死亡组大鼠脑组织5-HT均较对照组降低,1h组与12h组DA与对照组无统计学差异,24h组和死亡组比对照著升高。
3.1h组、24h组SOD高于对照组,12h组与对照组无统计学差异;死亡组低于对照组。
实验2:
1. TUNNEL染色各实验组与对照组无显著性差异。
2.各实验组大鼠脑组织Bcl-2/Bax均高于对照组。
3.各实验组大鼠脑组织Caspase-3均低于对照组。
实验3:
1.Ryr2的RT-PCR和免疫组化的结果均是1h组与对照组无统计学差异,12h组和24h组均高于对照组,随时间的延长,呈逐渐上升的趋势。
2. SERCA2的RT-PCR和免疫组化结果均是1h组、12h组和24h组高于对照组,随时间的延长,呈逐渐上升的趋势。
[结论]
1.MDMA染毒24h内,可诱发脑组织抗氧化物质SOD的生成及脑组织的抗凋亡效应。
2. MDMA染毒24h内,可诱发内质网Ca2+通道蛋白Ryr2和SERCA2的表达。
3.MDMA染毒24h内对脑组织有一定的保护作用,这种保护作用与抗氧化酶SOD、抗凋亡蛋白Bcl-2和内质网Ca2+通道蛋白的表达有关,且随着时间的延长,其保护作用有下降的趋势。
4.急性MDMA中毒死亡的大鼠,单胺类神经元损伤及氧化应激反应严重,其死亡机制可能与之有关。
[Objectives]
3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a ring-substituted phenylamine with very high abuse liability around the world. Many medico legists and toxicologists made researches on its mechanism of the toxicity. However, almost all of these studies were focus on the causes of the changes after abuse of MDMA24hours later. Whether does abuse of MDMA have any effects on organism within the first day? Little is understood about it. Some preclinical and clinical evidences show MDMA can made some users excited and leads to neurotoxic effects on central neurons only within a few minutes. For this reason, it is very necessary to study the changes on central nervous system for the first24hours after the consumption of MDMA. In order to find out the nervous effects within the first24hours, the subject made research on three probable aspects (oxidative stress, apoptosis and endoplasmic reticulum Ca2+channel) on brain tissue in rats.
[Methods] Part1:
1. An experiment model of forensic toxicology was set up under in vivo adult animal conditions, for administration of MDMA20mg/kg into abdominal cavity.32SD rats were supposed to be divided into experimental group(27rats) and control group(5rats). Then, all the rats in experimental group were consumed to be killed in three groups:1h,12h and24h after using MDMA.9rats in the1h group were executed. However,6rats died spontaneously during2-6h after injection of MDMA, which was named as spontaneous death group. The remaining rats were randomly divided into12h group(6rats) and24h group(6rats). The brain tissues of each group rats were taken out to reserve.
2. To analyze of5-HT and DA in three groups and spontaneous death group by High Performance Liquid Chromatography (HPLC).
3. To measure the activity of MDA in different groups by the method of TBA; to measure the activity of SOD by Hydroxylamine method. Part2:
1.1h group,12h group,24h group and contral group are the same as the part1.
2. To present rats' brain cells by HE and TUNNEL staining; to analyze of the proteins about apoptosis:bcl-2, bax and caspase-3by Western Blot and immumohistochemical staining. Part3:
1. To administration of drugs and to make groups as same as the part2.
2. To analyze the expression of Ryr2and SERCA2by the method of RT-PCR and immumohistochemical staining.
[Results] Part1:
1. Obvious toxic reactions were observed after administration of MDMA, and there was spontaneous death of rats in6hours with the mortality rate was22.22%.
2. MDMA administration produced significant decreases in only5-HT tissue content in each group, while there were significant grows in DA content in both24h group and spontaneous death group.
3. There were increases of SOD in1h and24h group comparing to the control group, while decline in spontaneous death group. Part2:
There was no significant difference in the number of apoptotic cells in each exposed group, while MDMA administration led to the bcl-2/bax ratio rising and caspase-3falling. Part3:
1. The analysis of Ryr2was1h group had no obvious change, but the contents in12h and24h groups increased significantly after MDMA abusing.
2. The expression of SERCA2was higher in exposed groups than control group.
3. The contents about expression and mRNA of Ryr2and SERCA2were increasing with time.
[Conclusions]
1. Disposable20mg/kg MDMA administration in rats can lead to the neurotoxicity on monoamine terminals and oxidative stress reaction in brain within24hours. Serious damages caused by MDMA maybe fatal.
2. MDMA administration produces the raising of antioxidative enzymes SOD and the effect of resistance to apoptosis.
3. MDMA administration can induce the expression of Ryr2and SERCA2who are endoplasmic reticulum Ca2+channel proteins.
4. Sublethal injury by MDMA can provide some protections on brain tissue. The mechanism of nervous protections is related with antioxidative enzymes SOD, anti-apoptotic protein Bcl-2and endoplasmic reticulum of Ca2+channel proteins.
引文
[1]Strote J, Lee JE, Wechsler H. Increasing MDMA use among college students: re-sults of a national survey [J]. J Adolesc Health.2002,30(1):64-72.
[2]Kliewer W, Murrelle L. Risk and protective factors for adolescent substance us e:findings from a study in selected Central American countries [J]. J Adolesc Healt h.2007,40(5):448-55.
[3]Wilkins C, Sweetsur P. Trends in population drug use in New Zealand:finding s from national house hold surveying of drug use in 1998,2001,2003, and 2006 [J]. N Z Med J.2008,121(1274):61-71.
[4]Norris TF, Eyeson-Annan ML. Recent substance use and high levels of psychol o-gycal distress among secondary school students in New South Wales [J]. N S W Public Health Bull.2007,18(7-8):125-129.
[5]Editorial team.2010. The EMCDDA annual report 2010:the state of the drugs problem in Europe. Euro Surveill.15:19714.
[6]Shimane T, Hidaka Y, Wada K, Funada M. Ecstasy (3,4- methylenedioxymetha m-phetamine) use among Japanese rave population. Psychiatry Clin Neurosci.2013, 67(1):12-19.
[7]张源泉,崔伟昌.济南市“摇头丸”犯罪的现状、特点及对策[J].山东公安专科学校学报.2003,71(5):83-85.
[8]刘强,吴意,蒋第二.毒尘大追踪[J].中国边防警察.2013,192(02):75-76.
[9]刘娟,王松才,徐淑云.MDMA中毒致死检验1例[J].法医学杂志,2009,25(03):237-238.
[10]刘彦,陆海华.“摇头丸”急性中毒抢救1例[J].第三军医大学学报.2005,27(11):1174.
[11]张书韬,姚仲义,郝利刚等.口服摇头丸后过度疲劳致心肌断裂死亡1例[J].刑事技术,2007,199(2):12.
[12]赵苳.亚甲二氧基甲基苯丙胺情况介绍[J].中国药物依赖性通报.1997,6(2):11 8-121.
[13]Quinton MS, Yamamoto BK. Causes and consequences of methamphetamine an d MDMA Toxicity [J]. AAPS J.2006,8(2):E337-47.
[14]Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4-methylenediox y-methamphetamine (ecstasy) [J]. Lancet.1992,340(8816):384-7.
[15]李素霞,黄明生.MDMA的神经毒性及其机理的研究进展[J].国际精神病学杂志.2005,32(3):162-165.
[16]Philip R. Forbidden drugs-understanding drug sand why people take them. Pu blished in the United States by Oxford University Press Inc. New York.1994:97-108.
[1]张西.苯丙胺类兴奋剂三次滥用高峰的历史嬗变[J].中国人民公安大学学报(自然科学版).2011.76(1):27-34.
[2]Morton J. Ecstasy:Pharmacology and neurotoxicity [J]. Curr Opin Pharmacol.2005. 5(1):79-86.
[3]Quinton MS, Yamamoto BK. Causes and consequences of methamphetamine and MDMA toxicity [J]. AAPS J.2006.8(2):E337-347.
[4]Colado MI, O'Shea E, Granados R, et al. In vivo evidence for free radical involvement in the degeneration of rat brain 5-HT following administration of MDMA ("ecstasy") and p-chloroamphetamine but not the degeneration following fenfluramine [J]. Br J Pharmacol. 1997.121(5):889-900.
[5]Shankaran M, Yamamoto BK, Gudelsky GA. Involvement of the serotonin transporter in the formation of hydroxyl radicals induced by 3,4-methylenedioxymethamphetamine [J]. Eur J Pharmacol.1999.385(2-3):103-110.
[6]Shankaran M, Yamamoto BK, Gudelsky GA. Mazindol attenuates the 3,4-methylenedioxymethamphetamine-induced formation of hydroxyl radicals and long-term depletion of serotonin in the striatum [J]. J Neurochem.1999.72(6):2516-2522.
[7]Kobeissy FH, Zhang Z, Sadasivan S, et al. Methods in drug abuse neuroproteomics: methamphetamine psychoproteome [J]. Methods Mol Biol.2009.566:217-228.
[8]王志云,肖玉芳,李素霞.3,4-亚甲基二氧基甲基苯丙胺对大鼠的神经毒性及维生素C的保护作用[J].中国新药杂志.2008.17(11):942-946.
[9]杨养贤,延卫东,乔晋等.对大鼠脑缺血再灌注脑组织超氧化物歧化酶和丙二醛的影响[J].中国临床康复.2004.8(28):6146-6147.
[10]de la Torre R, Farre M, Ortuno J, et al. Non-linear pharmacokinetics of MDMA (ecstasy) in humans [J]. Br J Clin Pharmacol.2000.49(2):104-109.
[11]陈锐.摇头丸(MDMA)的危害及其对免疫系统影响的研究进展[J].中国物证 学杂志.2009.9(7):1526-1528.
[12]Park BK. Cytochrome P450 enzymes in the heart [J].Lancet.2000.355(9208):945.
[13]Marc AS. Educating yourself about alcohol and drugs. Plenum Press.1994:280-285.
[14]Arthur K.C, David SS. Amphetamine and its analogs. Academic Press Inc.1994:59-60, 374-375.
[15]Philip R. Forbidden drugs-understanding drug sand why people take them. Oxford University Press Inc. New York.1994:97-108.
[16]邓书芳,吴守谦,蔡文瑛等.台湾缉获摇头丸中MDMA含量分析之研究[J].化学杂志.2005.63(3):463-480.
[17]周丽萍,贺东生.MDMA摇头丸对小鼠LD50的测定及其毒性作用[J].2005.30(5):41-42.
[18]Green AR, O'shea E, Colado MI. A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response [J]. Eur J Pharmacol. 2004.500(1-3):3-13.
[19]Steele TD, McCann UD, Ricaurte GA.3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"):pharmacology and toxicology in animals and humans [J]. Addiction. 1994.89(5):539-551.
[20]Parrott AC, Buchanan T, Scholey AB. Ecstasy/MDMA attributed problems reported by novice, moderate and heavy recreational users [J]. Human sychopharmacology:clin and exper.2002.17(6):309-312.
[21]Turillazzi E, Riezzo I, Neri M, et al. MDMA toxicity and pathological consequences:a review about experimental data and autopsy findings [J]. Curr Pharm Biotechnol. 2010.11(5):500-509.
[22]李陕区,杨博,许昌泰.神经递质5羟色胺研究现状[J].临床医学工程.2010.17(5):145-147.
[23]Rothman RB, Baumann MH. Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs [J]. Ann N Y Acad Sci. 2006.1074:245-260.
[24]Crespi D, Mennini T, Gobbi M. Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine,3,4-methylendioxymethamphetamine, p-chloroamphetamine and (+)-fenfluramine [J]. Br J Pharmacol.1997.121(8):1735-1743.
[25]Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin [J]. Synapse.2001.39(1):32-41.
[26]McCann UD, Szabo Z, Scheffel U, et al. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. Lancet. 1998.352(9138):1433-1437.
[27]Scanzello CR, Hatzidimitriou G, Martello AL, et al. Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine injury:observations in rats [J]. J Pharmacol ExpTher.1993.264(3):1484-1491.
[28]Aguirre N, Barrionuevo M, Ramirez MJ, et al. Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity [J]. Neuroreport. 1999.10(17):3675-3680.
[29]O'Shea E, Granados R, Esteban B, et al. The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (ecstasy) [J]. Neuropharmacology.1998.37(7):919-926.
[30]谭北平,李勇辉,隋南.药物依赖过程中多巴胺受体的作用及其研究进展[J].中国药物依赖性杂志.2003.12(2):81-85.
[31]Charles A, Marsden. Dopamine:the rewarding years [J]. B J Pharmacology. 2006.147:136-144.
[32]Leshner AL. Treating the brain in drug abuse [J]. NIDA Notes Direct.2000.15(4): 246-252.
[33]Biezonski DK, Piper BJ, Shinday NM, et al. Effects of a short-course MDMA binge on dopamine transporter binding and on levels of dopamine and its metabolites in adult male rats [J]. Eur J Pharmacol.2013.701(1-3):176-180.
[34]Orej arena MJ, Lanfumey L, Maldonado R, et al. Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behavior [J]. Int J Neuropsychopharmacol.2011.14(7):927-940.
[35]Hondebrink L, Meulenbelt J, Meijer M, et al. High concentrations of MDMA (ecstasy) and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells [J]. Neuropharmacology.2011.61(1-2):202-208.
[36]Bellomo G, Mirabelli F. Oxidative stress injury studied in isolated intact cells [J]. Mol Toxicol.1987-1988.1(4):281-293.
[37]Bai F, Jones DC, Lau SS, et al. Serotonergic neurotoxicity of 3,4-(+/-)-methylene-dioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase [J]. Chem Res Toxicol. 2001.14(7):863-780.
[38]Jones DC, Lau SS, Monks TJ. Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells [J]. J Pharmacol Exp Ther. 2004.3 11(1):298-306.
[39]Jiang XR, Wrona MZ, Alguindigue SS, Dryhurst G. Reactions of the putative neurotoxin tryptamine-4,5-dione with L-cysteine and other thiols. Chem Res Toxicol [J]. 2004.17(3):357-369.
[40]Michel PP, Hefti F. Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture [J]. J Neurosci Res.1990.26(4):428-435.
[41]Sprague JE, Everman SL, Nichols DE. An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine [J]. Neurotoxicology.1998. 19(3):427-441.
[42]Breier JM, Bankson MG, Yamamoto BK. L-tyrosine contributes to 3,4-methylene-dioxymethamphetamine induced serotonin depletions [J]. J Neurosci.2006. 26(1):290-299.
[43]Colado MI, Camarero J, Mechan AO, et al. A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on dopamineneurones in mouse brain [J]. Br J Pharmacol.2001.134(8):1711-1723.
[44]Darvesh AS, Yamamoto BK, Gudelsky GA. Evidence for the involvement of nitric oxide in 3,4-methylenedioxymethamphetamine-induced serotonin depletion in the rat brain [J]. J Pharmacol Exp Ther.2005.312(2):694-701.
[45]李素霞,黄明生.MDMA的神经毒性及其机理的研究进展[J].2005.32(3):162-165.
[46]Kikugawa CA. On refrigerating unused pitressin tannate in oil [J]. West J Med.1980. 132(2):165.
[47]Esterbauer H, Dieber-Rotheneder M, Waeg G, et al. Endogenous antioxidants and lipoprotein oxidation [J]. Biochem Soc Trans.1990.18(6):1059-1061.
[48]李勇.超氧化物歧化酶(SOD)的应用研究进展[J].攀枝花学院学报.2007.24(6):9-11.
[49]Koenig J, Lazarus C, Jeltsch H, et al. MDMA (ecstasy) effects in pubescent rats: Males are more sensitive than females [J]. Pharmacol Biochem Behav. 2005.81(3):635-644.
[1]Carson DA, Rieiro JM. Apoptosis and disease [J]. Lancet.1993.341(8855):1251-1254.
[2]郑德先.细胞凋亡的研究进展[J].中华病理学杂志.1996.1(25):50-53.
[3]Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs [J]. BMC Pharmacol.2006.6:6.
[4]Steele TD, McCann UD, Ricaurte GA.3,4-Methylenedioxy-methamphetamine (MDMA,"ecstasy"):pharmacology and toxicology in animals and humans [J]. Addiction. 1994.89(5):539-551.
[5]Jimenez A, Jorda EG, Verdaguer E, et al. Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells [J]. 2004.196(2):223-234.
[6]Capela JP, Fernandes E, Remiao F, et al. Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons [J]. Neurotoxicology. 2007.28(4):868-875.
[7]王雪,李静,祝三平.MDMA诱导大鼠神经元凋亡及凋亡相关因子caspase-3的表达[J].华西药学杂.志2007.22(5):511-513.
[8]弓娟琴,陈志强,李文忠等.Fas介导的凋亡与Caspase族[J].国外医学:肿瘤学分册.2001.27(5):279-280.
[9]Chai F, Truong-Tran AQ, Ho LH, et al. Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review [J]. Immunol Cell Biol.1999. 77(3):272-278.
[10]Lockshin RA. Programmed cell death:history and future of a concept [J]. J Soc Biol. 2005.199(3):169-173.
[11]Thornberry NA, Lazebnik Y. Caspases: enemies within [J]. Science.1998. 281(5381):1312-1316.
[12]Visconti R, Adagio L. Functional cloning of genes regulating apoptosis in neuronal cells [J]. Methods Mol Biol.2007.399:125-131.
[13]Kuribayashi K, Mayes PA, El-Deiry WS. What are caspases 3 and 7 doing upstream of the mitochondria [J]. Cancer Biol Ther.2006.5(7):763-765.
[14]许霖水.细胞抗凋亡信号转导[J].国外医学.2001.22(3):113-114.
[15]Tsujisaki M, Hinodo Y, Tosuchi S, et al. The analysis of internal image-bearing anti-idiotypic monoclonal antibody in relation to cartinoembryonic antigen [J]. J Immunol. 1993.2(150):508-516.
[16]Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis:apoptosomes or mitochondria [J]. Genes Cells.1998.3(11):697-707.
[17]Moreau C, Cartron PF, Hunt A. Minimal BH3 peptides promote cell death by antagonizing ant-i apoptotic proteins [J]. J Biol Chem.2003.278(21):19426-19435.
[18]De Falco M, De Luca L, Acanfora F, et al. Alteration of the Bcl-2:Bax ratio in the placenta as pregnancy proceeds [J]. Histochem J.2001.33(7):421-425.
[19]Raisova M, Hossini AM, Eberle J, et al. The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis [J]. J Invest Dermatol.2001.117(2):333-340.
[20]Gupta S. Molecular signaling in death receptor and mitochondrial pathways of apoptosis (Review) [J]. Int J Oncol.2003.22(1):15-20.
[21]Bayir H, Kagan VE. Bench-to-bedside review:Mitochondrial injury, oxidative stress and apoptosis--there is nothing more practical than a good theory [J]. Crit Care.2008. 12(1):206.
[22]Kroemer G Mitochondrial control of apoptosis:an overview [J]. Biochem Soc Symp. 1999.66:1-15.
[23]Crompton M. Mitochondrial intermembrane junctional complexes and their role in cell death [J]. J Physiol.2000.529[Ptl]:11-21.
[24]Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability [J]. Cell Death Differ.2000.7(12):1182-1191.
[25]Kuwana T, Mackey MR, Perkins G Bid, et al. Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane [J]. Cell.2002. 111(3):331-342.
[26]Mayer B, Oberbauer R. Mitochondrial regulation of apoptosis [J]. News Physiol Sci. 2003.18:89-94.
[27]王虎,蔡定芳.Ca2+与内质网途径的细胞凋亡[J].国际病理科学与临床杂志.2006.(25)4:283-285.
[28]王晓静.氧化应激相关的细胞凋亡过程中基因表达改变[J].国外医学(肿瘤学分册).2004.1:10-14.
[29]Sheng, Tanner X, Bump EA, et al. An oxidative stress mediated death pathway in irradiated human leukemia cells mapped using multilaser flow cytometry [J]. Radiat Res. 1998.150(6):636-647.
[30]Kane D, Sarafian TA, Anton R, et al. Bcl-2 inhibition of neural death:Decreased generation of reactive oxygen species [J]. Science.1993.5137(262):1274-1277.
[31]Piper BJ, Huyen LV, Safain MG, et al. Repeated adolescent 3,4-methylenedioxymethamphetamine (MDMA) exposure in rats attenuates the effects of a subsequent challenge with MDMA or a 5-hydroxytryptamine-1A receptor agonist [J]. J Pharmacol Exp Ther.2006.317:838-849.
[32]Nirmal SB, Jack L, Jacobi C, et al. Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain [J]. Brain Res.2009.1286:32-41.
[33]Riddle EL, Kokoshka JM, Wilkins DG, et al. Tolerance to the neurotoxic effects of methamphetamine in young rats [J]. Eur J Pharmacol 2002.435(2-3):181-185.
[34]Wang XD, Lu YL, Lai RC, et al. Protective effect of ketamine against acute rat lung injury induced by liopolysaccharide and its mechanism [J]. Nan Fang Yi Ke Da Xue Xue Bao.2007.27(12):1848-1850.
[35]Escobedo I, Peraile I, Orio L, et al. Evidence for a role of Hsp70 in the neuroprotection induced by heat shock pretreatment against 3,4-methylenedioxymethamphetamine toxicity in rat brain [J]. J Neurochem. 2007.101:1272-1283.
[36]Ceriello A, dello Russo P, Amstad P, et al. High glucose induces antioxidant enzymes in human endothelial cells in culture:Evidence linking hyperglycemia and oxidative stress [J]. Diabetes.1996.45(4):471-477.
[37]Schoeniger LO, Andreoni KA, Ott GR, et al. Induction of heat-shock gene expression in postischemic pig liver depends on superoxide generation [J]. Gastroenterology. 1994.106(1):177-184.
[38]Strand C, Warshaw JB, Snow K, et al. Heat shock does not induce tolerance to hyperoxia [J]. Lung.1994.172(2):79-89.
[39]师婷,宋维芳.热休克蛋白32对脑缺血再灌注损伤大鼠脑组织抗氧化能力的影响[J].2012.43(3):171-173.
[40]Samali A, Cotter TG. Heat shock proteins increase resistance to apoptosis[J]. Experimental Cell Research.1996.223(1):163-170.
[41]Hughes PE, AlexiT, YoshidaT, et al. Excitotoxic lesion of rat brainwith quinolinic acid induces expression of p53 messenger RNA and protein and p53 inducible genes Bax and Gadd 45 in brain areas showing DNA fragmentation [J]. Neuroscience.1996. 74(4):1143-1160.
[42]曲凌云,孙修勤,相建海等.热休克蛋白研究进展[J].海洋科学进展.2004.3(8):385-391.
[1]东方,高世勇,季宇彬.Ca2+介导的细胞凋亡通路研究进展[J].齐齐哈尔医学院学报.2008.29(13):1602-1604.
[2]Hanson CJ, Bootman MD, Roderick HL. Cell signalling:IP3 receptors channel calcium into cell death [J]. Curr Biol.2004.14(21):933-935.
[3]Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death:the calcium-apoptosis link [J]. Nat Rev Mol Cell Biol.2003.4(7):552-565.
[4]Schneider T, Perez-Reyes E, Nyormoi O, et al. Alpha-1 subunits of voltage gated Ca2+ channels in the mesencephalon x neuroblastoma hybrid cell line MES23.5 [J]. Neuroscience.1995.68(2):479-485.
[5]Rusin KI, Moises HC.Mu-opioid and GABA(B) receptors modulate different types of Ca2+currents in rat nodose ganglion neurons [J]. Neuroscience.1998.85(3):939-956.
[6]施建婷.神经变性过程中钙稳态变化与氧化应激初步研究:[硕士学位论文].华东师范大学,2009.
[7]Hondebrink L, Meulenbelt J, Meijer M, et al. High concentrations of MDMA ('ecstasy') and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells [J]. Neuropharmacology.2011.61(1-2):202-208.
[8]章晓辉,朱培闳.Ryanodine受体结构和药理学性质生理科学进展[J].1997.28(3):224-228.
[9]Murayama T, Ogawa Y. Properties of Ryr3 ryanodine receptor isoform in mammalian brain [J]. J Biol Chem.1996.271(9):5079-5084.
[10]Verkhratsky A, Shmigol A. Calcium-induced calcium release in neurons [J]. Cell Calcium.1996.19(1):1-14.
[11]Giannini G, Conti A, Mammarella S, et al. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues [J]. J Cell Biol.1995.128(5):893-904.
[12]高益宁.若干钙调控蛋白在小鼠ES细胞衍生神经元内质网钙储存及神经发生中 的作用:[硕士学位论文].浙江大学,2012.
[13]Ogawa Y. Role of ryanodine receptors [J]. Crit Rev Biochem Mol Biol. 1994.29(4):229-274.
[14]Xiao B, Tian X, Xie W, et al. Functional consequence of protein kinase A-dependent phosphorylation of the cardiac ryanodine receptor:sensitization of store overload-induced Ca2+release [J]. J Biol Chem.2007.282(41):30256-30264.
[15]Murayama T, Ogawa Y. Characterization of type 3 ryanodine receptor (Ryr3) of sarcoplasmic reticulum from rabbit skeletal muscles [J]. J Biol Chem.1997. 272(38):24030-24037.
[16]Igami K, Yamaguchi N, Kasai M. Regulation of depolarization-induced calcium release from skeletal muscle triads by cyclic AMP-dependent protein kinase [J]. Jpn J Physiol.1999.49(1):81-87.
[17]Rousseau E, Smith JS, Meissner G. Ryanodine modifies conductance and gating behavior of single Ca2+ release channel [J]. Am J Physiol.1987.253(3 Pt 1):C364-368.
[18]Copello JA, Barg S, Sonnleitner A, et al. Differential activation by Ca2+, ATP and caffeine of cardiac and skeletal muscle ryanodine receptors after block by Mg2+[J]. J Membr Biol.2002.187(1):51-64.
[19]Fruen BR, Bardy JM, Byrem TM, et al. Differential Ca(2+) sensitivity of skeletal and cardiac muscle ryanodine receptors in the presence of calmodulin [J]. Am J Physiol Cell Physiol.2000 Sep;279(3):C724-233.
[20]夏若虹,姚松年,李莉.1,4萘醌和谷胱甘肽对Ryanodine受体初始结合率的影响及其意义[J].生物物理学报.1999.15(4):667-674.
[21]Finnegan KT, Taraska T. Effects of glutamate antagonists on methamphetamine and 3,4-methylenedioxymethamphetamineinduced striatal dopamine release in vivo [J]. J Neurochem.1996.66(5):1949-1958.
[22]Mark KA, Soghomonian JJ, Yamamoto BK. High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity [J]. J Neurosci.2004.24(50):11449-11456.
[23]Sattler R, Tymianski M. Molecular mechanisms of calcium dependent excitotoxicity [J]. J Mol Med.2000.78(1):3-13.
[24]Baba-Aissa F, Raeymaekers L, Wuytack F, et al. Distribution and isoform diversity of the organellar Ca2+ pumps in the brain [J]. Mol Chem Neuropathol.1998.33(3):199-208.
[25]吴淞.钙离子对心脏的反常作用[J].生理科学进展.1985.56(1):32-35.
[26]秦晓群,孙秀乱.气道平滑肌收缩性能的细胞内调控[J].生理科学进展.1992.70(1):67-69.
[27]毕坎华,申华,刘一仙等.硒对心肌质膜(Ca2+,Mg2+)-ATPase和肌浆网Ca2+-ATPase活体的影响[J].生物化学杂志.1992.8(4):385-389.
[28]史以庆.花生四烯酸及其代谢物的生理与药理[J].生理科学进展.1985.56(1):66-67.
[29]Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility [J]. J Mol Cell Cardiol.2001.33(6):1053-1063.
[30]H(?)yer-Hansen M, Bastholm L, Szyniarowski P, et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2 [J]. Mol Cell.2007. 25(2):193-205.
[31]赵序利,刘艳华,罗剑刚等.异氟醚通过激活Ryanodine受体对ReNcell CX人神经干细胞损伤和存活发挥双向调节作用[J].2012.2(9):11-13.
[32]唐璐,张智博.内质网应激与脑缺血再灌注损伤[J].实用预防医学.2008.15(3):963-968.
[33]王海英,张秋玲,白波.内质网应激及其相关性凋亡与缺血注脑损伤[J].泰山医学院学报.2008.29(5):390-393.
[34]Schroder M, Kaufman RJ. ER stress and unfolded protein response [J]. Muta Rec, 2005.569(1-2):29-63.
[35]Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development:friend or foe? [J]. Nat Rev Cancer.2004.4(12):966-977.
[36]Rao RV, Bredesen DE. Misfolded protein, endoplasmic reticulum stress and neuro degeneration [J]. Curr Opin Struct Biol.2004.16(6):653-662.
[37]Ron D. Translational control in the endoplasmic reticulum stress response [J]. J Clin Invest,2002,110(10):1383-1388.
[38]关丽英,许彩民,潘华珍.内质网应激介导的细胞凋亡[J].生物化学与生物物理进展.2007,34(11):1136-1141.
[39]Verkhratsky A, Petersen OH. The endoplasmic reticulum as an integrating signaling organelle:from neuronal signaling to neuronal death [J]. Eur J pharmacol. 2002.447(2-3):141-154.
[40]Distelhorst CW, McCormick TS. Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells [J]. Cell Calcium.1996.19(6):473-483.
[41]Monaco G, Vervliet T, Akl H, et al. The selective BH4-domain biology of Bcl-2-family members:IP3Rs and beyond [J]. Cell Mol Life Sci.2013.70(7):1171-1183.
[1]Shulgin AT. The background and chemistry of MDMA [J]. J Psychoactive Drugs.1986. 18(4):291-304.
[2]Davis WM, Hatoum HT, Waters IW. Toxicity of MDA (3, 4-methylenedioxyamphetamine) considered for relevance to hazards of MDMA (Ecstasy) abuse [J]. Alcohol Drug Res.1987.7(3):123-134.
[3]Climko RP, Roehrich H, Sweeney DR, et al. Ecstacy:a review of MDMA and MDA [J]. Int J Psychiatry Med.1986-1987.16(4):359-72.
[4]Strote J, Lee JE, Wechsler H. Increasing MDMA use among college students:results of a national survey [J]. J Adolesc Health.2002.30(1):64-72.
[5]Wish ED, Fitzelle DB, OG'rady KE, et al. Evidence for significant polydrug use among ecstasy-using college students [J]. J Am Coll Health.2006.55(2):99-104.
[6]Editorial team. The EMCDDA annual report 2010:the state of the drugs problem in Europe. Euro Surveill.2010.15:19714.
[7]Shimane T, Hidaka Y, Wada K, et al. Ecstasy (3,4-methylenedioxymethamphetamine) use among Japanese rave population [J]. Psychiatry Clin Neurosci.2013.67(1):12-9.
[8]Kliewer W, Murrelle L. Risk and protective factors for adolescent substance use: findings from a study in selected Central American countries [J]. J Adolesc Health.2007. 40(5):448-55.
[9]Wilkins C, Sweetsur P, Griffiths R. Recent trends in pharmaceutical drug use among frequent injecting drug users, frequent methamphetamine users and frequent ecstasy users in New Zealand 2006-2009 [J]. Drug Alcohol Rev.2011.30(3):255-263.
[10]张源泉,崔伟.济南市“摇头丸”犯罪的现状、特点及对策[J].山东公安专科学校学报.2003.71(5):83-85.
[11]刘强,吴意,蒋第二.毒尘大追踪[J].中国边防警察.2013.02:75-76.
[12]蒋和平,任川宏.MDMA分子结构与性质的密度泛函理论研究[J].西华大学学报(自然科学版).2006.25(5):69-70.
[13]秦总根.摇头丸(MDMA)的危害及其分析检验[J].2006.6(1):19-22.
[14]Marc AS. Educating yourself about alcohol and drugs. Plenum Press.1994:280-285.
[15]Arthur KC, David SS. Amphetamine and its analogs. Academic Press Inc.1994:59-60, 374-375.
[16]Philip R. Forbidden drugs-understanding drug sand why people take them. Oxford University Press Inc. New York.1994:97-108.
[17]李龙辉,顾钧,蒋树龙等.亚甲二氧甲基苯丙胺的临床前行为药理学作用[J].2005.4(6):353-356,372.
[18]Stone DM, Stahl DC, Hanson GR, et al. The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain [J]. Eur J Pharmacol.1986. 128(1-2):41-8.
[19]Barenys M, Flick B, Boix N, et al. Effects of MDMA (ecstasy) and two of its metabolites on rat embryos in vitro [J]. Reprod Toxicol.2012.34(1):57-65.
[20]Scheidweiler KB, Ladenheim B, Barnes AJ, et al. (±)-3,4-methylenedioxymethamphetamine and metabolite disposition in plasma and striatum of wild-type and multidrug resistance protein 1α knock-out mice [J]. J Anal Toxicol.2011.35(7):470-80.
[21]Crespi D, Mennini T, Gobbi M. Carrier-dependent and Ca2+-dependent 5-HT and dopamine release induced by (t)-amphetamine,3,4-methylendioxymethamphetamine, p-chloroamphetamine and (t)-fenfluramine [J]. Br J Pharmacol.1997.121(8):1735-43.
[22]Johnson MP, Hoffman AJ, Nichols DE. Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices [J]. Eur J Pharmacol.1986.132(2-3):269-76.
[23]Battaglia G, Sharkey J, Kuhar MJ, et al. Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography [J]. Synapse.1991.8(4):249-260.
[24]Scanzello CR, Hatzidimitriou G, Martello AL, et al. Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine injury:observations in rats [J]. J Pharmacol Exp Ther.1993.264(3):1484-1491.
[25]Mueller M, Yuan J, Felim A, et al. Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity [J]. Drug Metab Dispos.2009.37(10):2079-2086.
[26]Escobedo I, O'Shea E, Orio L, et al. A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice [J]. Br J Pharmacol.2005.144(2):231-241.
[27]Gartside S E, Mc Quade R, Sharp T. Effects of repeated administration of 3,4-methylenedioxymethamphetamine on 5-hydroxytryptamine neuronalactivity and release in the rat brain in vivo [J]. J Pharmacol Exp Ther.1996.279(1):277-283.
[28]Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs [J]. BMC Pharmacol.2006.3(6):6.
[29]Biezonski DK, Piper BJ, Shinday NM, et al. Effects of a short-course MDMA binge on dopamine transporter binding and on levels of dopamine and its metabolites in adult male rats [J]. Eur J Pharmacol.2013.701(1-3):176-180.
[30]Schmidt CJ, Levin JA, Lovenberg W. In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain [J]. Biochem Pharmacol.1987.36(5):747-755.
[31]Nash JF, Brodkin J. Microdialysis studies on 3,4-methylenedioxymethamphetamine induced dopamine release:effect of dopamine uptake inhibitors [J]. J Pharmacol Exp Ther. 1991.259(2):820-825.
[32]Hondebrink L, Meulenbelt J, Meijer M, et al. High concentrations of MDMA (ecstasy) and its metabolite MDA inhibit calcium influx and depolarization-evoked vesicular dopamine release in PC12 cells [J]. Neuropharmacology.2011.61(1-2):202-208.
[33]Orejarena MJ, Lanfumey L, Maldonado R, et al. Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behavior [J]. Int J Neuropsychopharmacol.2011.14(7):927-940.
[34]Steele TD, McCann UD, Ricaurte GA.3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"):pharmacology and toxicology in animals and humans [J]. Addiction. 1994.89(5):539-551.
[35]McCann UD, Szabo Z, Scheffel U, et al. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. Lancet. 1998.352(9138):1433-1437.
[36]王雪,彭祖贵,况伟宏等.3,4-亚甲基二氧基甲基苯丙胺神经毒性的实验研究[J].中国临床康复.2004.8(31):6916-6917.
[37]Michel PP, Hefti F. Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture [J]. J Neurosci Res.1990.26(4):428-435.
[38]Sprague JE, Everman SL, Nichols DE. An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine [J]. Neurotoxicology.1998. 19(3):427-441.
[39]Breier JM, Bankson MG, Yamamoto BK. L-tyrosine contributes to 3,4-methylenedioxymethamphetamine-induced serotonin depletions [J]. J Neurosci.2006. 26(1):290-299.
[40]Darvesh AS, Yamamoto BK, Gudelsky GA. Evidence for the involvement of nitric oxide in 3,4-methylenedioxymethamphetamine-induced serotonin depletion in the rat brain [J]. J Pharmacol Exp Ther.2005.312(2):694-701.
[41]Kuhn DM, Sadidi M, Liu X. Peroxynitrite-induced nitration of tyrosine hydroxylase: identification of tyrosines 423,428 and 432 assites of modification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and tyrosine-scanning mutagenesis [J]. J Biol Chem.2002.277(16):14336-14342.
[42]Colado MI, Camarero J, Mechan AO, et al. A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on dopamineneurones in mouse brain [J]. Br J Pharmacol.2001.134(8):1711-1723.
[43]李素霞,黄明生.MDMA的神经毒性及其机理的研究进展[J].2005.32(3):162-165.
[44]Darvesh AS, Shankaran M, Gudelsky GA.3,4-Methylenedioxymethamphetamine produces glycogenolysis and increases the extracellular concentration of glucose in the rat brain [J]. J Pharmacol Exp Ther.2002.301(1):138-144.
[45]卢延旭,郑少攀,纪丽颖等.MDMA对原代培养乳鼠脑皮质神经元的损伤机制[J].2006.31(4):193-195,190.
[46]Burrows KB, Gudelsky G, Yamamoto BK. Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration [J]. Eur J Pharmacol.2000. 398(1):11-18.
[47]Nixdorf WL, Burrows KB, Gudelsky GA, et al. Enhancement of 3,4-methylenedioxymethamphetamine neurotoxicity by the energy inhibitor malonate [J]. J Neurochem.2001.77(2):647-654.
[48]Quinton MS, Yamamoto BK. Causes and consequences of methamphetamine and MDMA toxicity [J]. AAPS J.2006.8(2):E337-E347.
[49]Finnegan KT, araska T. Effects of glutamate antagonists on methamphetamine and 3,4-methylenedioxymethamphetamineinduced striatal dopamine release in vivo [J]. J Neurochem.1996.66(5):1949-1958.
[50]Sattler R, Tymianski M. Molecular mechanisms of calcium dependent excitotoxicity [J]. J Mol Med (Berl).2000.78(1):3-13.
[51]Lafon CM. NMD dependent superoxide production and neurotoxicity [J]. Nature. 1993.364(6437):535.
[52]Mattson MP and M Sherman. Perturbed signal transduction in neurodegenerative disorders involving aberrant Protein aggregation [J]. Neuro Med.2003.4(1-2):109-132.
[53]Green AR, O'shea E, Colado MI. A review of the mechanisms involved in the acute MDMA(ecstasy) induced hyperthermic response [J]. Eur J Pharmacol.2004. 500(1-3):3-13.
[54]Green AR, Medchan AO, Elliott JM, et al. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") [J]. Pharmacol Rev.2003.55(3):463-508.
[55]Mechan AO, Esteban B, O'Shea E, et al. The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") to rats [J]. Br. J. Pharmacol.2002.135(1):170-180.
[56]Liechti ME, Vollenweider, FX. Acute psychological and physiological effects of MDMA (Ecstasy) after haloperidol pretreatment in healthy humans [J]. Eur Neuropsychopharmacol.2000.10(4):289-295.
[57]Carvalho M, Carvalho F, Remiao F, et al. Effect of 3,4-methylenedioxymetham phetamine (ecstasy) on body temperature and liver antioxidant status in mice:influence of ambient temperature [J]. Arch Toxicol.2002.76(3):166-172.
[58]Johnson EA, Shvedova AA, Kisin E, et al. d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity [J]. Brain Res.2002. 933(2):150-163.
[59]O'Shea E, Esteban B, Camarero J, et al. Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA (ecstasy) on the 5-HT and dopamine concentrations in mouse brain [J]. Neuropharmacology.2001.40(1):65-74.
[60]Saadat KS, Elliott JM, Colado MI, et al. Hyperthermic and neurotoxic effect of 3,4-methylenedioxymethamphetamine (MDMA) in guinea pigs [J]. Psychopharmacology (Berl).2004.173(3-4):452-453.
[61]Liechti ME, Vollenweider FX. The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (Ecstasy) in healthy volunteers [J]. J. Psychopharmacol.2000.14(3):269-274.
[62]Mas M, Farre M, de la Torre R, et al. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine in humans [J]. J Pharmacol Exp Ther.1999.290(1):136-145.
[63]Orio L, O'Shea E, Sanchez V, et al.3,4-Methylenedioxymethamphetamine (MDMA) increases IL-1 P levels and activates microglia in rat brain:studies on the relationship with acute hyperthermia and 5-HT depletion [J]. J. Neurochem.2004.89(6):1445-1453.
[64]Colado MI, Murray TK, Green AR.5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine [J]. Br J Pharmacol.1993. 108(3):583-589.
[65]Orio L, O'Shea E, Sanchez V, et al.9.3,4-Methylenedioxymethamphetamine increases interleukin-lbeta levels and activates microglia in rat brain:studies on the relationship with acute hyperthermia and 5-HT depletion [J]. J Neurochem.2004.89(6):1445-1453.
[66]Kluger MJ. Fever:role of pyrogens and cryogens [J]. Physiol Rev.1991.71(1):93-127.
[67]Malberg JE, Seiden LS. Small changes in ambient temperature cause large changes in 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat [J]. J. Neurosci.1998.18(13):5086-5094.
[68]Dafters RI. Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4-methylenedioxymethamphetarnine (MDMA or ecstasy) in rats [J]. Psychopharmacology.1994.114(3):505-508.
[69]Dafters RI, Lynch E. Persistent loss of thermoregulation in the rat induced by 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) but not by fenfluramine [J]. Psychopharmacology.1998.138(2):207-212.
[70]Broening HW, Bowyer JF, Slikker JW. Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (F)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response [J]. J Pharmacol Exp Ther.1995.275(1):325-333.
[71]Jones AL, Simpson KJ. Review article:mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications [J]. Aliment Pharmacol Ther.1999.13(2):129-133.
[72]Carvalho M, Milhazes N, Remiao F, et al. Hepatotoxicity of 3,4-methylenedioxyamphetamine and alpha-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates [J]. Arch Toxicol.2004.78(1):16-24.
[73]Holt MP, Ju C. Mechanisms of drug-induced liver injury [J]. AAPS J.2006. 8(1):E48-54.
[74]Tucker GT, Lennard MS, Ellis SW, et al. The demethylenation of methylenedioxymethamphetamine (ecstasy) by debrisoquine hydroxylase (CYP2D6) [J]. Biochem Pharmacol.1994.47(7):1151-1156.
[75]de la Torre R, Farre M, Ortuno J, et al. Non-linear pharmacokinetics of MDMA (ecstasy) in humans [J]. Br J Clin Pharmacol.2000.49(2):104-109.
[76]Carvalho M, Pontes H, Remiao F, et al. Mechanisms underlying the hepatotoxic effects of ecstasy [J]. Curr Pharm Biotechnol.2010.11(5):476-495.
[77]Jones DC, Duvauchelle C, Ikegami A, et al. Serotonergic neurotoxic metabolites of ecstasy identified in rat brain [J]. J Pharmacol Exp Ther.2005.313(1):422-431.
[78]Meyer MR, Peters FT, Maurer HH. The role of human hepatic cytochrome P450 isozymes in the metabolism of racemic 3,4-methylenedioxy-methamphetamine and its enantiomers [J]. Drug Metab Dispos.2008.36(11):2345-2354.
[79]Antolino-Lobo I, Meulenbelt J, Nijmeijer SM, et al. Differential roles of phase I and phase II enzymes in 3,4-methylendioxymethamphetamine-induced cytotoxicity [J]. Drug Metab Dispos.2010.38(7):1105-1112.
[80]Monks TJ, Lau SS. Biological reactivity of polyphenolic glutathione conjugates [J]. Chem Res Toxicol.1997.10(12):1296-1313.
[81]Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians [J]. J Pharmacol Exp Ther.1994.270(1):414-423.
[82]Zhang Y, Bachmeier C, Miller DW. In vitro and in vivo models for assessing drug efflux transporter activity [J]. Adv Drug Deliv Rev.2003.55(1):31-51.
[83]Li AP. Evaluation of luciferin-isopropyl acetal as a CYP3A4 substrate for human hepatocytes:effects of organic solvents, cytochrome P450 (P450) inhibitors, and P450 inducers [J]. Drug Metab Dispos.2009.37(8):1598-1603.
[84]Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor:a key regulator of xenobiotic metabolism [J]. Endocr Rev.2002.23:687-702.
[85]Hewitt NJ, Lecluyse EL, Ferguson SS. Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro-in vivo correlations [J]. Xenobiotica. 2007.37(10-11):1196-1224.
[86]Das BC, Madhukumar AV, Anguiano J, et al. Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR) [J]. Bioorg Med Chem Lett.2008.18(14):3974-3977.
[87]Moore LB, Maglich JM, McKee DD, et al. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors [J]. Mol Endocrinol.2002.16(5):977-986.
[88]Ekins S, Chang C, Mani S, et al. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites [J]. Mol Pharmacol.2007. 72(3):592-603.
[89]Maurer HH, Bickeboeller-Friedrich J, Kraemer T, et al. Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs ("Ecstasy") [J]. Toxicol Lett.2000. 112-113:133-142.
[90]de la Torre R, Farre M, Navarro M, et al. Clinical pharmacokinetics of amphetamine and related substances:monitoring in conventional and non-conventional matrices [J]. Clin Pharmacokinet.2004.43(3):157-185.
[91]Shoda T, Fukuhara K, Goda Y, et al.4-Hydroxy-3-methoxymethamphetamine glucuronide as a phase II metabolite of 3,4-methylenedioxymethamphetamine: enzyme-assisted synthesis and involvement of human hepatic uridine 50-diphosphate-glucuronosyltransferase 2B15 in the glucuronidation [J]. Chem Pharm Bull.2009.57(5): 472-475.
[92]Peters JM, Rusyn I, Rose ML, et al. Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells:implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis [J]. Carcinogenesis.2000. 21(4):823-826.
[93]Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands:new insights on cellular and molecular mechanisms [J]. Trends Immunol.2007.28(12):551-558.
[94]Yessoufou A, Wahli W. Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels [J]. Swiss Med Wkly. 2010.140:wl3071.
[95]Pontes H, Duarte JA, de Pinho PG, et al. Chronic exposure to ethanol exacerbates MDMA-induced hyperthermia and exposes liver to severe MDMA-induced toxicity in CD1 mice [J]. Toxicology.2008.252(1-3):64-71.
[96]Droogmans S, Cosyns B, D'Haenen H, et al. Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease [J]. Am J Cardiol 2007.100(9):1442-1445.
[97]Setola V, Hufeisen SJ, Grande-Allen KJ, et al.3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenflurarnine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol.2003.63(6):1223-1229.
[98]Mayama T, Matsumura K, Lin H, et al. Remodelling of cardiac gap junction connexin 43 and arrhythmogenesis [J]. Exp Clin Cardiol.2007,12(2):67-76.
[99]潘伊凡,王严冬,周红.生脉注射液治疗摇头丸中毒心律失常10例[J].河南中医.2006.07:68-69.
[100]王雪,彭祖贵,况伟宏等.3,4-二甲亚氧基甲基苯丙胺的机体毒性研究[J].华西医学.2004.19(3):415-416.
[101]赵忠桂,李雅欣.MDMA(3,4-亚甲基二氧甲基苯丙胺)对小鼠睾丸组织DNA的损伤[J].河南预防医学杂志.2013.24(1):13-14.