O'Shea E, Esteban B, Camarero J, Green A R, Colado M I
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain.
Neuropharmacology. 2001;40(1):65-74. doi: 10.1016/s0028-3908(00)00106-4.
We examined the long term effect of 3,4 methylenedioxymethamphetamine (MDMA, 10, 20 and 30 mg/kg, i.p.) on the cerebral 5-hydroxytryptamine (5-HT) and dopamine content in Swiss Webster mice. Three injections of MDMA (20 or 30 mg/kg, i.p.) given 3 h apart produced a marked depletion in the striatal content of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) 7 days later. None of the doses administered altered the concentration of 5-HT or its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in several brain areas. Pre-treatment with the dopamine uptake inhibitor GBR 12909 (10 mg/kg, i.p.), 30 min before each of the three MDMA (30 mg/kg, i.p.) injections, completely prevented the long term loss in the striatal catechol concentrations. However, GBR 12909 (10 mg/kg, i.p.) not only failed to prevent the acute effects induced by MDMA (30 mg/kg x 3, i.p.) on dopamine metabolism 30 min later, but in fact potentiated them. The 5-HT uptake inhibitor, fluoxetine (10 mg/kg, i. p.) failed to prevent both the acute and long term dopaminergic deficits. MDMA (30 mg/kg x 3) altered the body temperature of the mice biphasically, producing a rapid hyperthermia followed by prolonged hypothermia. In contrast, MDMA (20 mg/kg x 3) produced an initial hypothermia followed by hyperthermia. The present experiments therefore appear to rule out any direct relationship between the neurotoxic effects of MDMA and its acute effects on body temperature in mice. Fluoxetine administered 30 min before each MDMA (30 mg/kg) injection prevented these temperature changes, while GBR 12909 was without effect. This suggests that the neuroprotective effect of GBR 12909 against MDMA-induced neurotoxicity is not directly related to its ability to inhibit the MDMA-induced acute effects on dopamine metabolism or alter the MDMA-induced temperature change. The data illustrate major differences in the neurotoxic profile of MDMA in mice and rats.
我们研究了3,4－亚甲基二氧甲基苯丙胺（摇头丸，10、20和30毫克/千克，腹腔注射）对瑞士韦伯斯特小鼠脑内5－羟色胺（5－HT）和多巴胺含量的长期影响。每隔3小时腹腔注射3次摇头丸（20或30毫克/千克），7天后纹状体内多巴胺及其代谢产物3,4－二羟基苯乙酸（DOPAC）和高香草酸（HVA）的含量显著减少。所给予的任何剂量均未改变几个脑区中5－HT或其代谢产物5－羟吲哚乙酸（5－HIAA）的浓度。在3次腹腔注射摇头丸（30毫克/千克）每次前30分钟，用多巴胺摄取抑制剂GBR 12909（10毫克/千克，腹腔注射）进行预处理，可完全防止纹状体内儿茶酚浓度的长期降低。然而，GBR 12909（10毫克/千克，腹腔注射）不仅未能防止30分钟后摇头丸（30毫克/千克×3，腹腔注射）对多巴胺代谢诱导的急性效应，实际上反而使其增强。5－HT摄取抑制剂氟西汀（10毫克/千克，腹腔注射）未能防止急性和长期多巴胺能缺陷。摇头丸（30毫克/千克×3）使小鼠体温产生双相变化，先是迅速体温过高，随后是长时间体温过低。相比之下，摇头丸（20毫克/千克×3）先是体温过低，随后体温过高。因此，本实验似乎排除了摇头丸的神经毒性作用与其对小鼠体温的急性效应之间的任何直接关系。在每次腹腔注射摇头丸（30毫克/千克）前30分钟给予氟西汀可防止这些体温变化，而GBR 12909则无作用。这表明GBR 12909对摇头丸诱导的神经毒性的神经保护作用与其抑制摇头丸对多巴胺代谢的急性效应或改变摇头丸诱导的体温变化的能力无直接关系。数据表明摇头丸在小鼠和大鼠中的神经毒性特征存在主要差异。
