There is a lack of data on the effects of chronic exposure to common drugs and stimulants on the developing nervous system. Freshwater planarians have emerged as a useful invertebrate model amenable to high-throughput behavioral phenotyping to assay chemical safety in adult and developing brains. Here, we leverage the unique strength of the system to test in parallel for effects on the adult and developing nervous system, by screening ten common drugs and stimulants (forskolin, clenbuterol, LRE-1, MDL-12,330A, adenosine, caffeine, histamine, mianserin, fluoxetine and sertraline) using the asexual freshwater planarian Dugesia japonica. The compounds were tested up to 100 µM nominal concentration for their effects on planarian morphology and behavior. Quantitative phenotypic assessments were performed on days 7 and 12 of exposure using an automated screening platform. The antidepressants sertraline and fluoxetine were the most potent to induce lethality, with significant lethality observed at 10 µM. All ten compounds caused sublethal morphological and/or behavioral effects, with the most effects, in terms of potency and breadth of endpoints affected, seen with mianserin and fluoxetine. Four of the compounds (forskolin, clenbuterol, mianserin, and fluoxetine) were developmentally selective, causing effects at lower concentrations in regenerating planarians. Of these, fluoxetine showed the greatest differences between the two developmental stages, inducing many behavioral endpoints in regenerating planarians but only a few in adult planarians. While some of these behavioral effects may be due to neuroefficacy, these results substantiate the need for better evaluation of the safety of these common drugs on the developing nervous system.

中文翻译：

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成年涡虫和再生涡虫对慢性药物暴露的反应不同

缺乏关于长期接触常见药物和兴奋剂对发育中的神经系统的影响的数据。淡水涡虫已成为一种有用的无脊椎动物模型，适用于高通量行为表型分析，以测定成人和发育中大脑的化学安全性。在这里，我们利用该系统的独特优势，通过筛选十种常见药物和兴奋剂（毛喉素、瘦肉精、LRE-1、MDL-12,330A、腺苷、咖啡因、组胺）来平行测试对成人和发育中的神经系统的影响，mianserin，氟西汀和舍曲林）使用无性淡水涡虫Dugesia japonica. 测试了高达 100 µM 标称浓度的化合物对涡虫形态和行为的影响。使用自动筛选平台在暴露的第 7 天和第 12 天进行定量表型评估。抗抑郁药舍曲林和氟西汀是最有效的致死剂，在 10 µM 时观察到显着的致死率。所有十种化合物均引起亚致死的形态学和/或行为影响，在效力和受影响终点的广度方面影响最大，见于米安色林和氟西汀。其中四种化合物（毛喉素、克仑特罗、米安色林和氟西汀）具有发育选择性，在较低浓度下对涡虫的再生产生影响。其中，氟西汀在两个发育阶段之间表现出最大的差异，在再生涡虫中诱导许多行为终点，但在成年涡虫中只有少数。虽然其中一些行为影响可能是由于神经功效，但这些结果证实需要更好地评估这些常见药物对发育中的神经系统的安全性。