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IRAS抗阿片依赖作用及其神经生物学机制

Chinese Journal of Pharmacology and Toxicology(2023)

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Abstract
目的 咪唑啉受体抗体选择性蛋白(IRAS)是I1咪唑啉受体(I1R)功能性候选蛋白.本课题旨在研究IRAS在调节谷氨酸系统的作用,进而为阐明IRAS调节阿片依赖神经生物学机制及其作为抗阿片依赖药物靶标提供实验依据.方法 应用生物素标记实验、活细胞成像等技术,研究IRAS对基础状态和吗啡慢性处理下谷氨酸AMPA受体GluA1亚基在神经元突触后膜表达和定位的影响;应用条件性位置偏爱、催促戒断以及认知行为测试等实验,研究IRAS对于阿片依赖及其引起学习记忆障碍的影响.在此基础上,研究I1R/IRAS内源性配体胍丁胺对阿片依赖的影响.结果 IRAS敲除显著增加基础状态和吗啡慢性处理后AMPA受体在神经元突触后膜表达和定位,并且其作用与AMPA受体GluA1亚基ser845磷酸化和PSD95表达有关.IRAS调节作用关键脑区为伏隔核,IRAS敲除导致伏隔核基础状态AMPA/NMDA比率增加而吗啡慢性处理后比率降低.IRAS敲除小鼠在吗啡慢性给药下表现出精神依赖、躯体依赖增加、Y迷宫记忆损伤增加,AMPA受体拮抗剂能够显著降低野生型小鼠阿片依赖行为,而对IRAS敲除小鼠作用显著降低.外源性胍丁胺给药能够降低吗啡精神依赖和躯体依赖行为,其作用与结合IRAS相关,提示IRAS能够作为抗阿片依赖潜在干预靶点.结论 IRAS抗阿片依赖作用与调节AMPA受体作用相关,可能作为潜在干预靶标发挥抗阿片依赖作用.
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