Department of Pediatric Surgery, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Shantou, 515041, Guangdong, China; Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong, China; Guangdong Key Laboratory of Medical Molecular Imaging, No. 57 Changping Road, Shantou, 515041, Guangdong, China.
Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Shantou, 515041, Guangdong, China; Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong, China; Guangdong Key Laboratory of Medical Molecular Imaging, No. 57 Changping Road, Shantou, 515041, Guangdong, China.
Behav Brain Res. 2020 Sep 1;393:112796. doi: 10.1016/j.bbr.2020.112796. Epub 2020 Jul 4.
Drug addiction continues to threaten the health and welfare of people worldwide, and ephedrine abuse is a serious drug problem in many areas of the world. Ephedrine toxicity is thought to induce behavioral effects primarily through actions on the central nervous system. The corticotropin-releasing factor (CRF) system plays an important role in regulating behavioral effects induced by addictive drugs, but whether CRF is related to ephedrine toxicity remains unclear. This study seeks to examine whether there is a correlation between the CRF and chronic ephedrine neurotoxicity. To this end, we established a chronic ephedrine (0.4-1.6 mg/kg/d) exposure model in rhesus macaques, assessed its effects on body weight and behavior, examined neuronal changes in the prefrontal cortex and hippocampus, and measured the CRF expression in the prefrontal cortex and hippocampus. After 8-weeks of exposure to ephedrine, the toxic effects of ephedrine included significant weight loss and induction of behavioral changes in rhesus macaques. In particular, in the modeling group, the abnormal behavioral changes mainly manifested as irritability and behavioral sensitization. Meanwhile, the histological abnormalities included neuronal morphological changes, pyknosis and irregular shapes of neurons in the prefrontal cortex and hippocampus. In addition, the expression levels of CRF mRNA and protein were increased in the prefrontal cortex and hippocampus of ephedrine-treated animals. In summary, the finding of this study indicated that ephedrine neurotoxicity can cause neuronal damage in cerebral cortex, which in turn can result in certain neurobehavioral abnormalities, and that CRF expression in prefrontal cortex and hippocampus is elevated in response to ephedrine exposure. These observations suggested that long-term exposure to ephedrine might be causing neurotoxicity and leading to neurobehavioral disorders accompanied by up-regulation of CRF in prefrontal cortex and hippocampus.
药物成瘾继续威胁着全世界人民的健康和福祉，而麻黄碱滥用是世界许多地区的一个严重毒品问题。人们认为，麻黄碱毒性主要通过对中枢神经系统的作用来诱导行为效应。促肾上腺皮质激素释放因子 (CRF) 系统在调节成瘾药物诱导的行为效应方面起着重要作用，但 CRF 是否与麻黄碱毒性有关尚不清楚。本研究旨在探讨 CRF 是否与慢性麻黄碱神经毒性有关。为此，我们建立了恒河猴慢性麻黄碱（0.4-1.6mg/kg/d）暴露模型，评估其对体重和行为的影响，观察前额叶皮质和海马神经元变化，并测量前额叶皮质和海马的 CRF 表达。在暴露于麻黄碱 8 周后，麻黄碱的毒性作用包括明显的体重减轻和诱导恒河猴行为改变。特别是在模型组中，异常行为改变主要表现为易怒和行为敏感化。同时，组织学异常包括前额叶皮质和海马神经元形态改变、固缩和神经元形状不规则。此外，CRF mRNA 和蛋白的表达水平在麻黄碱处理动物的前额叶皮质和海马中增加。总之，这项研究的发现表明，麻黄碱神经毒性可导致大脑皮层神经元损伤，进而导致某些神经行为异常，而前额叶皮质和海马中 CRF 的表达在暴露于麻黄碱后升高。这些观察结果表明，长期暴露于麻黄碱可能导致神经毒性，并导致伴有前额叶皮质和海马中 CRF 上调的神经行为障碍。
