下调和上调
铁转运蛋白
甲基苯丙胺
缺氧(环境)
药理学
化学
缺氧诱导因子
海西定
泛素
DMT1型
有条件地点偏好
药品
多巴胺
内分泌学
内科学
医学
运输机
贫血
生物化学
氧气
有机化学
基因
作者
Pengju Yan,Ningning Li,Mengmeng Ma,Zhaoli Liu,Hui‐Jun Yang,Jinnan Li,Chunlei Wan,Shan Gao,Shuai Li,Longtai Zheng,John L. Waddington,Xu Lin,Xuechu Zhen
标识
DOI:10.1038/s41392-023-01578-2
摘要
Abstract Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the upregulation of Hypoxia-inducible factor-1α (HIF-1α) expression by roxadustat (Rox), a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α, administered either systemically or locally into selected brain regions, suppressed morphine (Mor)-induced conditioned place preference (CPP). A similar effect was observed with methamphetamine (METH). Moreover, Rox also inhibited the expression of both established and reinstated Mor-CPP and promoted the extinction of Mor-CPP. Additionally, the elevation of HIF-1α enhanced hepcidin/ferroportin 1 (FPN1)-mediated iron efflux and resulted in cellular iron deficiency, which led to the functional accumulation of the dopamine transporter (DAT) in plasma membranes due to iron deficiency-impaired ubiquitin degradation. Notably, iron-deficient mice generated via a low iron diet mimicked the effect of Rox on the prevention of Mor- or METH-CPP formation, without affecting other types of memory. These data reveal a novel mechanism for HIF-1α and iron involvement in substance use disorder, which may represent a potential novel therapeutic strategy for the treatment of drug abuse. The findings also repurpose Rox by suggesting a potential new indication for the treatment of substance use disorder.
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