Chemistry and Drug Metabolism, Intramural Research Program, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard Suite 200, Room 05A-721, Baltimore, MD 21224, USA.
Neurotox Res. 2010 Aug;18(2):200-9. doi: 10.1007/s12640-009-9124-z. Epub 2009 Oct 23.
Multidrug resistance protein 1a (MDR1a) potentiated methylenedioxymethamphetamine (MDMA)-induced decreases of dopamine (DA) and dopamine transport protein in mouse brain one week after MDMA administration. In the present study, we examined if mdr1a wild-type (mdr1a +/+) and knock-out (mdr1a -/-) mice differentially handle the acute effects of MDMA on the nigrostriatal DA system 0-24 h following a single drug injection. 3-way ANOVA revealed significant 2-way interactions of strain x time (F (5,152) = 32.4, P < 0.001) and strain x dose (F (3,152) = 25.8, P < 0.001) on 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios in mdr1a +/+ and -/- mice. 0.3-3 h after 10 mg/kg MDMA, DOPAC/DA ratios were increased in mdr1a +/+ mice, but decreased 0.3-1 h after MDMA in mdr1a -/- mice. Twenty-four hours after 10 mg/kg MDMA, DOPAC/DA ratios were increased 600% in mdr1a +/+ mice compared to saline-treated control mice, while in mdr1a -/- mice DOPAC/DA ratios were unchanged. Striatal MDMA and its metabolite, methylenedioxyamphetamine, concentrations by gas chromatography-mass spectrometry were similar in both strains 0.3-4 h after MDMA, discounting the role of MDR1a-facilitated MDMA transport in observed inter-strain differences. Increased DOPAC/DA turnover in mdr1a +/+ mice following MDMA is consistent with the previous report that MDMA neurotoxicity is increased in mdr1a +/+ mice. Increased DA turnover via monoamine oxidase in mdr1a +/+ vs -/- mice might increase exposure to neurotoxic reactive oxygen species.
多药耐药蛋白 1a（MDR1a）增强了亚甲二氧基甲基苯丙胺（MDMA）在给药后一周内对小鼠大脑中多巴胺（DA）和多巴胺转运蛋白的降低作用。在本研究中，我们检查了 mdr1a 野生型（mdr1a +/ +）和敲除（mdr1a -/-）小鼠是否在单次药物注射后 0-24 小时内对 MDMA 对黑质纹状体 DA 系统的急性影响有不同的处理方式。3 因素方差分析显示，在 mdr1a +/ +和-/-小鼠中，应激 x 时间（F（5,152）= 32.4，P <0.001）和应激 x 剂量（F（3,152）= 25.8，P <0.001）有显著的 2 因素相互作用。在 mdr1a +/ +小鼠中，0.3-3 小时后，3,4-二羟基苯乙酸（DOPAC）/DA 比值升高，但在 mdr1a -/-小鼠中，0.3-1 小时后降低。在 10mg/kg MDMA 后 24 小时，mdr1a +/ +小鼠中 DOPAC/DA 比值增加了 600%，而 mdr1a -/-小鼠中 DOPAC/DA 比值不变。与生理盐水处理的对照小鼠相比，mdr1a +/ +小鼠在 10mg/kg MDMA 后 24 小时时 DOPAC/DA 比值增加了 600%，而 mdr1a -/-小鼠中 DOPAC/DA 比值不变。在 MDMA 后 0.3-4 小时，两种品系的纹状体 MDMA 和其代谢物亚甲二氧基苯丙胺的浓度通过气相色谱-质谱法相似，排除了 MDR1a 促进 MDMA 转运在观察到的品系差异中的作用。在 MDMA 后 mdr1a +/ +小鼠中 DOPAC/DA 周转率的增加与之前的报告一致，即 mdr1a +/ +小鼠中 MDMA 的神经毒性增加。mdr1a +/ +与-/-小鼠中通过单胺氧化酶增加的 DA 周转率可能会增加对神经毒性活性氧的暴露。
