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

多药耐药蛋白 1a (MDR1a) 在甲基苯丙胺和亚甲基中的作用

• 批准号: 7966918
• 负责人: Karl Scheidweiler
• 金额: $ 15.39万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7966918
• 关键词: Affect; Amphetamines; Back; Blood - brain barrier anatomy; Brain; Carrier Proteins; Dopamine; Drug Transport; Goals; High Pressure Liquid Chromatography; Knock-out; Knockout Mice; Learning; Mass Fragmentography; Measures; Memory impairment; Methamphetamine; Neurotransmitters; Norepinephrine; P-Glycoproteins; Pathway interactions; Pharmaceutical Preparations; Plasma; Play; Poison; Property; Proteins; Reporting; Role; Serotonin; Testing; Western Blotting; Wild Type Mouse; brain cell; cell injury; dopamine transporter; ecstasy; human subject; neurotoxicity; neurotransmitter transport; psychostimulant

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.

甲基苯丙胺（Methamphetamine，METH）是一种精神兴奋剂，可导致大脑中神经递质多巴胺和多巴胺转运蛋白的长期耗竭。 多巴胺和多巴胺转运蛋白的减少可能会导致精神发育迟缓和记忆障碍。 亚甲二氧基甲基苯丙胺（MDMA，摇头丸）是一种苯丙胺衍生药物，具有兴奋剂和致幻特性。 虽然MDMA在结构上与METH相似，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，报告大量使用摇头丸的人类受试者记忆和学习能力长期受损。 多药耐药蛋白1a（MDR 1a）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转运回血脑屏障，从而保护脑细胞免受损伤。 我们推测METH和MDMA的MDR 1a转运在药物神经毒性中起作用。 该项目使用mdr 1a基因敲除小鼠和野生型小鼠来确定1）MDR 1a对METH和MDMA的转运是否会导致METH或MDMA脑浓度的改变，以及2）这些脑浓度的改变是否与METH或MDMA给药后的神经毒性相关。 将使用气相色谱-质谱法测量给予METH或MDMA后mdr 1a基因敲除小鼠和野生型小鼠脑和血浆中METH、MDMA和代谢物的浓度。 将使用高效液相色谱法测量给予METH或MDMA后mdr 1a基因敲除小鼠和野生型小鼠脑中的神经递质浓度。 此外，还将通过蛋白质印迹法测量脑中神经递质转运蛋白的水平。