Long-term exposure to ephedrine leads to neurotoxicity and neurobehavioral disorders accompanied by up-regulation of CRF in prefrontal cortex and hippocampus in rhesus macaques
Long-term exposure to ephedrine leads to neurotoxicity and neurobehavioral disorders accompanied by up-regulation of CRF in prefrontal cortex and hippocampus in rhesus macaques
复制标题
长期接触麻黄碱会导致恒河猴神经毒性和神经行为障碍，并伴有前额皮质和海马 CRF 上调
DOI：
10.1016/j.bbr.2020.112796
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发表时间：
2020-09-01
影响因子：
2.7
通讯作者：
Ma，Shuhua
中科院分区：
文献类型：
--
作者：
Duan，Shouxing;Xie，Lei;Ma，Shuhua
吸毒成瘾继续威胁着全世界人民的健康和福祉，滥用麻黄素是世界许多地区的一个严重毒品问题。麻黄碱毒性被认为主要通过对中枢神经系统的作用引起行为效应。促肾上腺皮质激素释放因子（CRF）系统在成瘾性药物的行为效应中起着重要的调节作用，但CRF是否与麻黄碱毒性有关尚不清楚。本研究旨在检查CRF和慢性麻黄碱神经毒性之间是否存在相关性。为此，我们在恒河猴中建立了慢性麻黄碱（0.4-1.6 mg/kg/d）暴露模型，评估了其对体重和行为的影响，检查了前额叶皮层和海马神经元的变化，并测量了前额叶皮层和海马中CRF的表达。暴露于麻黄碱8周后，麻黄碱的毒性作用包括显著的体重减轻和诱导恒河猴的行为变化。尤其是造模组，其异常行为改变主要表现为易激惹和行为敏感化。组织学异常表现为前额叶皮质和海马神经元形态学改变、核固缩、形态不规则。此外，CRFmRNA和蛋白质的表达水平增加，在前额叶皮层和海马的马槟榔治疗的动物。综上所述，本研究的结果表明，麻黄碱神经毒性可引起大脑皮层神经元损伤，这反过来又可导致某些神经行为异常，并在前额叶皮层和海马CRF的表达升高，以响应麻黄碱暴露。这些观察结果表明，长期暴露于麻黄碱可能会导致神经毒性，并导致神经行为障碍，伴随着在前额皮质和海马CRF的上调。
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.