Behavioral changes and neuronal damage in rhesus monkeys after ten weeks ketamine administration involve prefrontal cortex dopamine D2 receptor and dopamine transporter
Behavioral changes and neuronal damage in rhesus monkeys after ten weeks ketamine administration involve prefrontal cortex dopamine D2 receptor and dopamine transporter
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施用氯胺酮十周后恒河猴的行为变化和神经元损伤涉及前额皮质多巴胺 D2 受体和多巴胺转运蛋白
DOI：
10.1016/j.neuroscience.2019.07.022
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发表时间：
2019
期刊：
影响因子：
3.3
通讯作者：
Shuhua Ma
中科院分区：
文献类型：
--
作者：
Zongbo Sun;Ye Ma;Lei Xie;Jinzhuang Huang;Shouxing Duan;Ruiwei Guo;Yao Xie;Junyao Lv;Zhirong Lin;Shuhua Ma
多巴胺D2受体（DRD2）和多巴胺转运蛋白（DAT）在多巴胺能神经传递中发挥调节作用，从而在药物成瘾中发挥重要作用。前额皮质（PFC）是中脑多巴胺能系统的关键部分，被认为参与药物成瘾的发展和维持。人们认为对氯胺酮的成瘾主要通过对中枢神经系统的作用来引起行为影响。然而，氯胺酮成瘾影响的神经机制仍不清楚。在这项研究中，我们研究了非人灵长类动物服用氯胺酮 10 周后 PFC DRD2 和 DAT 在氯胺酮成瘾效应中的作用。为此，在给恒河猴施用氯胺酮 10 周后，我们评估了体重和行为的变化。此外，通过苏木精和伊红 (HE) 染色检查 PFC 中的神经元变化。分别通过实时PCR和蛋白质印迹分析测定PFC中DRD2和DAT mRNA和蛋白表达水平。服用氯胺酮10周后，对恒河猴的毒性表现进行评估，发现体重和行为发生显着变化，前额皮质中DRD2和DAT mRNA和蛋白表达降低，以及前额皮质中神经元嗜酸性粒细胞增多、固缩和排列紊乱等组织学异常。这些结果表明，PFC中DRD2和DAT表达的减少可能参与了氯胺酮引起的行为和神经学变化，这可能在氯胺酮成瘾的分子机制中发挥重要作用。
The dopamine D2 receptor (DRD2) and dopamine transporter (DAT) play a regulatory role in dopaminergic neurotransmission and thus play an important role in drug addiction. The prefrontal cortex (PFC), a critical part of the mesencephalic dopaminergic system, is thought to be involved in the development and maintenance of drug addiction. The addiction to ketamine is thought to induce behavioral effects primarily through actions on the central nervous system. However, the neural mechanism underlying the effects of ketamine addiction remains unclear. In this study, we investigate the involvement of PFC DRD2 and DAT in ketamine addiction effects after ketamine administration for 10 weeks in nonhuman primates. To this end, after administering ketamine to rhesus monkeys for 10 weeks, we assessed changes in body weight and behavior. Additionally, neuronal changes in the PFC were examined by hematoxylin and eosin (HE) staining; the DRD2 and DAT mRNA and protein expression levels in the PFC were determined by real-time PCR and Western blot analysis, respectively. After 10-week ketamine administration, the assessment of the manifestations of toxicity in rhesus monkeys revealed significant changes in body weight and behavior, decreased DRD2 and DAT mRNA and protein expression in the PFC, and histological abnormalities including neuronal eosinophilia, pyknosis and disorderly arrangement of neurons in the PFC. These results suggest that the reduced expression of DRD2 and DAT in PFC could be involved in the behavioral and the neurological changes induced by ketamine administration, which may play an important role in the molecular mechanisms of ketamine addiction.