Effects of acute and chronic arecoline in adult zebrafish: Anxiolytic-like activity, elevated brain monoamines and the potential role of microglia
Effects of acute and chronic arecoline in adult zebrafish: Anxiolytic-like activity, elevated brain monoamines and the potential role of microglia
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DOI：
10.1016/j.pnpbp.2020.109977
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发表时间：
2021-01-10
影响因子：
5.6
通讯作者：
Kalueff, Allan, V
中科院分区：
文献类型：
--
作者：
Serikuly, Nazar;Alpyshov, Erik T.;Kalueff, Allan, V
槟榔碱是一种天然存在的精神活性生物碱，对烟碱和毒蕈碱乙酰胆碱受体具有部分激动作用。槟榔碱的消费很普遍，使其成为人类第四大使用物质（仅次于酒精，尼古丁和咖啡因）。然而，槟榔碱在体内的急性和慢性作用的机制仍然知之甚少。动物模型是CNS疾病建模和药物筛选的有价值的工具。补充啮齿动物研究，斑马鱼（Danio rerio）成为神经科学研究的一种有前途的新型模式生物。在这里，我们评估了急性和慢性槟榔碱对成年斑马鱼行为和生理的影响。总的来说，急性和慢性槟榔碱治疗产生了明显的抗焦虑样行为（不影响一般运动活动和全身皮质醇水平），槟榔水提取物也产生了类似的效果。急性槟榔碱在10毫克/升扰乱浅滩，增加社会偏好，脑去甲肾上腺素和血清素水平升高，降低血清素周转。急性槟榔碱还上调了大脑中的早期原癌基因c-fos和c-jun，而1 mg/L的慢性治疗升高了小胶质细胞特异性生物标志物基因egr 2和ym 1的大脑表达（因此，暗示了长期槟榔碱使用的潜在影响中的小胶质细胞机制）。最后，急性2小时停止慢性槟榔碱治疗引起的斑马鱼戒断样焦虑行为。总的来说，这些发现支持斑马鱼筛选槟榔碱和相关化合物的高灵敏度，并加强了斑马鱼用于探测CNS药物分子机制的日益增长的效用。我们的研究还表明，新的抗焦虑药物，最终可以开发的基础上阿托伐他汀样分子，其综合机制的中枢神经系统的行动可能涉及单胺能和神经免疫调节。
Arecoline is a naturally occurring psychoactive alkaloid with partial agonism at nicotinic and muscarinic acetylcholine receptors. Arecoline consumption is widespread, making it the fourth (after alcohol, nicotine and caffeine) most used substance by humans. However, the mechanisms of acute and chronic action of arecoline in-vivo remain poorly understood. Animal models are a valuable tool for CNS disease modeling and drug screening. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a promising novel model organism for neuroscience research. Here, we assessed the effects of acute and chronic arecoline on adult zebrafish behavior and physiology. Overall, acute and chronic arecoline treatments produced overt anxiolytic-like behavior (without affecting general locomotor activity and whole-body cortisol levels), with similar effects also caused by areca nut water extracts. Acute arecoline at 10 mg/L disrupted shoaling, increased social preference, elevated brain norepinephrine and serotonin levels and reduced serotonin turnover. Acute arecoline also upregulated early protooncogenes c-fos and c-jun in the brain, whereas chronic treatment with 1 mg/L elevated brain expression of microglia-specific biomarker genes egr2 and ym1 (thus, implicating microglial mechanisms in potential effects of long-term arecoline use). Finally, acute 2-h discontinuation of chronic arecoline treatment evoked withdrawal-like anxiogenic behavior in zebrafish. In general, these findings support high sensitivity of zebrafish screens to arecoline and related compounds, and reinforce the growing utility of zebrafish for probing molecular mechanisms of CNS drugs. Our study also suggests that novel anxiolytic drugs can eventually be developed based on arecoline-like molecules, whose integrative mechanisms of CNS action may involve monoaminergic and neuro-immune modulation.