Effects of Chronic Ephedrine Toxicity on Functional Connections, Cell Apoptosis, and CREB-Related Proteins in the Prefrontal Cortex of Rhesus Monkeys
Effects of Chronic Ephedrine Toxicity on Functional Connections, Cell Apoptosis, and CREB-Related Proteins in the Prefrontal Cortex of Rhesus Monkeys
复制标题
慢性麻黄碱毒性对恒河猴前额皮质功能连接、细胞凋亡和CREB相关蛋白的影响
DOI：
10.1007/s12640-019-00146-3
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发表时间：
2020-03-01
影响因子：
3.7
通讯作者：
Ma, Shuhua
中科院分区：
文献类型：
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作者：
Duan, Shouxing;Ma, Ye;Ma, Shuhua
麻黄碱滥用已在世界许多地区蔓延，严重威胁人类健康。麻黄碱的毒性机制尚不清楚。为了探讨麻黄碱毒性可能的神经机制，本研究建立了非人灵长类动物麻黄碱暴露模型，通过静息态BOLD-fMRI分析其前额叶皮质功能连接的变化，进而检测其病理生理变化以及环磷酸腺苷反应元件结合蛋白（CREB）、磷酸化CREB（P-CREB）和CREB靶蛋白（c-fos和fosB）的表达。前额皮质。麻黄碱中毒后，我们发现猴子的前额皮质与执行动机、驱动、奖励、学习和记忆功能的大脑区域的功能连接增强，而与执行认知控制的大脑区域的功能连接减弱。这些结果表明，麻黄碱毒性会导致神经回路异常，导致药物相关线索的放大和增强以及认知控制功能的减弱和损害。组织学表明麻黄碱的神经细胞毒性可引起神经元变性和凋亡。实时PCR和Western blot显示，麻黄碱中毒后前额皮质中CREB mRNA和CREB/P-CREB/c-fos/fosB蛋白表达增加。总的来说，本研究表明，药物暴露后神经回路异常引起的药物相关线索增强和认知控制减弱可能是麻黄碱引起脑功能变化的主要机制。这些组织学和分子变化可能是麻黄碱引起脑功能改变的病理生理基础。
Ephedrine abuse has spread in many parts of the world, severely threatening human health. The mechanism of ephedrine toxicity is still unclear. To explore the possible neural mechanisms of ephedrine toxicity, this study established a non-human primate model of ephedrine exposure, analyzed the functional connectivity changes in its prefrontal cortex through resting state BOLD-fMRI, and then inspected the pathophysiological changes as well as the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phosphorylated CREB (P-CREB), and CREB target proteins (c-fos and fosB) in the prefrontal cortex. After ephedrine toxicity, we found that the prefrontal cortex of monkeys strengthened its functional connectivity with the brain regions that perform motivation, drive, reward, and learning and memory functions and weakened its functional connectivity with the brain regions that perform cognitive control. These results suggest that ephedrine toxicity causes abnormal neural circuits that lead to the amplification and enhancement of drug-related cues and the weakening and damage of cognitive control function. Histology showed that the neurocytotoxicity of ephedrine can cause neuronal degeneration and apoptosis. Real-time PCR and Western blot showed increased expression of CREB mRNA and CREB/P-CREB/c-fos/fosB protein in the prefrontal cortex after ephedrine toxicity. Collectively, the present study indicates that the enhancement of drug-related cues and the weakening of cognitive control caused by abnormal neural circuits after drug exposure may be a major mechanism of brain function changes caused by ephedrine. These histological and molecular changes may be the pathophysiological basis of brain function changes caused by ephedrine.