Role of multidrug resistance protein 1a (MDR1a) in methamphetamine and methylened

甲基苯丙胺(METH)是一种精神刺激剂，会导致大脑中神经递质多巴胺和多巴胺转运蛋白的长期枯竭。多巴胺和多巴胺转运蛋白的减少可能会导致精神运动减慢和记忆障碍。亚甲基二氧基甲基苯丙胺(MDMA，摇头丸)是一种苯丙胺衍生的药物，具有兴奋剂和致幻作用。尽管MDMA在结构上类似于冰毒，但MDMA的效果不同。MDMA影响多种神经递质通路，包括5-羟色胺、多巴胺和去甲肾上腺素。研究表明，在报告大量使用MDMA的人类受试者中，记忆和学习长期受损。多药耐药蛋白1a(MDR1a)是一种位于血脑屏障(BBB)中的蛋白质，可以将大脑中的特定有毒物质通过血脑屏障转运回来，从而保护脑细胞免受损害。我们推测MDR1a转运冰毒和MDMA在药物神经毒性中起作用。该项目使用mdr1a基因敲除和野生型小鼠来确定1)MDR1a运输冰毒和MDMA是否会导致大脑中冰毒或MDMA浓度的变化，以及2)这些变化的大脑浓度是否与冰毒或MDMA注射后的神经毒性有关。气相色谱-质谱法将用于检测mdr1a基因敲除小鼠和野生型小鼠服用冰毒或MDMA后，大脑和血浆中冰毒、MDMA和代谢物的浓度。高效液相色谱法将被用来测量mdr1a基因敲除小鼠和野生型小鼠在注射冰毒或MDMA后大脑中的神经递质浓度。此外，还将通过Western blotting测量大脑中神经递质运输蛋白的水平。

Methamphetamine (METH) is a psychostimulant causing prolonged depletion of the neurotransmitter dopamine and dopamine transporter protein in brain. Decreases in dopamine and dopamine transporter protein may cause psychomotor slowing and memory impairments. Methylenedioxymethamphetamine (MDMA, ecstasy) is an amphetamine-derived drug that possesses stimulant and hallucinogenic properties. Although, MDMA is structurally similar to METH, MDMAs effects differ. MDMA affects multiple neurotransmitter pathways, including serotonin, dopamine and norepinephrine. Studies have demonstrated long-term impairments of memory and learning in human subjects reporting heavy MDMA use. Multidrug resistance protein 1a (MDR1a) is a protein located in the blood-brain barrier (BBB) that can transport specific toxic substances in the brain back across the BBB, thereby protecting brain cells from damage. We hypothesize that MDR1a transport of METH and MDMA plays a role in the drugs neurotoxicity. This project uses mdr1a knock-out and wild-type mice to determine 1) whether transport of METH and MDMA by MDR1a results in altered brain concentrations of METH or MDMA and 2) whether these altered brain concentrations correlate with neurotoxicity following METH or MDMA administration. Gas chromatography-mass spectrometry will be used to measure concentrations of METH, MDMA and metabolites in brain and plasma of mdr1a knock-out and wild-type mice following administration of METH or MDMA. High-performance liquid chromatography will be used to measure neurotransmitter concentrations in brains of mdr1a knock-out and wild-type mice after administration of METH or MDMA. Furthermore, levels of neurotransmitter transport proteins in brain also will be measured via Western blotting.