BACKGROUND MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. METHODS Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. RESULTS Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. CONCLUSION Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.

中文翻译：

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剂量和环境在启动和增强MDMA引起的大鼠神经毒性中的不同作用。

背景技术MDMA在给药后几天或几周内立即引起5-羟色胺（5-HT）综合征和血清素能损伤。然而，5-羟色胺综合征并不总是伴随着血清素能损伤，表明造成两种不良反应的机制不同。本研究的目的是确定两个不良事件的原因，并进一步测试剂量和环境在引发和增强MDMA神经毒性方面具有不同的作用。方法通过在控制环境下比较大剂量（2 mg / kg×3）和大剂量（10 mg / kg×3，间隔2 h）的神经毒性作用，来研究其启动和增强作用。通过测量脑脊髓液中的细胞外5-HT，体温，脑电图和MDMA浓度来估计血清素综合征的发作，而在改良环境下检查大鼠时确定的强化。通过测量组织5-HT含量，SERT密度和血清素能逆行转运的功能完整性，评估了大鼠血清素能损伤的起始和加剧。结果低剂量和高剂量均可引起细胞外5-HT升高，从而以相同的强度引发5-羟色胺综合征。对MDMA引起的5-HT水平升高没有影响的环境条件的改变显着加剧了综合征的强度。尽管在改良的环境下，任何一种剂量都会导致严重的综合症，但只有导致大脑中MDMA浓度高的高剂量才可能导致血清素能损伤。结论我们的研究结果表明，细胞外5-HT是综合征的原因，而突触后受体的活性对于综合征加剧的过程至关重要。尽管由于脑中存在高的MDMA浓度，大剂量有可能引发血清素能性损伤，但是否观察到损伤取决于药物环境，其取决于产生的活性氧的水平。这表明脑MDMA浓度是损伤开始的决定因素，而活性氧的产生与损伤加剧有关。结论是，这两种不良事件在毒性引发和加剧过程中利用了截然不同的介导分子。尽管由于脑中存在高的MDMA浓度，大剂量有可能引发血清素能性损伤，但是否观察到损伤取决于药物环境，其取决于产生的活性氧的水平。这表明脑MDMA浓度是损伤开始的决定因素，而活性氧的产生与损伤加剧有关。结论是，这两种不良事件在毒性引发和强化过程中​​利用了截然不同的介导分子。尽管由于脑中存在高的MDMA浓度，大剂量有可能引发血清素能性损伤，但是否观察到损伤取决于药物环境，其取决于产生的活性氧的水平。这表明脑MDMA浓度是损伤开始的决定因素，而活性氧的产生与损伤加剧有关。结论是，这两种不良事件在毒性引发和加剧过程中利用了截然不同的介导分子。这表明脑MDMA浓度是损伤开始的决定因素，而活性氧的产生与损伤加剧有关。结论是，这两种不良事件在毒性引发和加剧过程中利用了截然不同的介导分子。这表明脑MDMA浓度是损伤开始的决定因素，而活性氧的产生与损伤加剧有关。结论是，这两种不良事件在毒性引发和加剧过程中利用了截然不同的介导分子。