A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') on dopamine neurones in mouse brain
A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') on dopamine neurones in mouse brain
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DOI：
10.1038/sj.bjp.0704435
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发表时间：
2001-12-01
影响因子：
7.3
通讯作者：
Green, AR
中科院分区：
文献类型：
--
作者：
Colado, MI;Camarero, J;Green, AR
给小鼠服用3，4-亚甲二氧基甲基苯丙胺（MDMA，迷魂药）可引起急性体温过高和纹状体多巴胺神经末梢的长期变性。热疗的减弱可减轻神经变性。我们已经研究了纹状体多巴胺神经毒性损失的机制。2 MDMA在7天后以25 mg/kg（-1）的剂量给药3次，纹状体多巴胺浓度出现剂量依赖性损失。（间隔3小时）产生70%的损失。3在每次MDMA给药前30分钟用N-甲基-D-天冬氨酸拮抗剂AR-R15896 AR预处理（20、5、5 mg kg（-1））或MK-801（0.5 mg kg（-1）x 3）未能提供神经保护。4用氯甲噻唑预处理（50 mg kg（-1）× 3）在防止MDMA诱导的多巴胺丢失方面同样无效。5自由基捕获化合物PBN（150 mg kg（-1）× 3）具有神经保护作用，但证明不可能将神经保护作用与对体温的低温效应分开。6用一氧化氮合酶（NOS）抑制剂7-NI预处理（50 mg kg（-1）× 3）产生神经保护作用，但也显着降低体温。其他两种NOS抑制剂，S-甲基-L-硫代瓜氨酸（10 mg kg（-1）x 3）和AR-R17477AR（5 mg kg（-1）x 3），提供了显著的神经保护作用，对MDMA诱导的高血压几乎没有影响。（20 mg kg（-1））增加了通过植入纹状体的微透析管灌注水杨酸的2，3-二羟基苯甲酸形成，表明自由基形成增加。AR-R17477 AR给药阻止了这种增加。由于还发现AR-R17477 AR没有自由基捕获活性，因此该结果表明MDMA诱导的神经毒性是由MDMA或多巴胺代谢物产生自由基引起的，这些自由基与NO联合收割机结合形成组织损伤性过氧亚硝酸盐。
1 Administration of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine.2 MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg(-1) (3 h apart) producing a 70% loss.3 Pretreatment 30 min before each MDMA dose with either of the N-methyl-D-aspartate antagonists AR-R15896AR (20, 5, 5 mg kg(-1)) or MK-801 (0.5 mg kg(-1)x 3) failed to provide neuroprotection.4 Pretreatment with clomethiazole (50 mg kg(-1) x 3) was similarly ineffective in protecting against MDMA-induced dopamine loss.5 The free radical trapping compound PBN (150 mg kg(-1) x 3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature.6 Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg(-1) x 3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg(-1) x 3) and AR-R17477AR (5 mg kg(-1)x 3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia.7 MDMA (20 mg kg(-1)) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue-damaging peroxynitrites.