Rationale

Preclinical and clinical reports suggest that ferulic acid (FA), a plant-derived phenylpropanoid, is effective against mental health problems such as agitation, anxiety, and irritability in humans, without causing adverse side effects. However, the mechanism of action is unknown.

Objective

The aim of the study is to investigate the mechanism underlying the ameliorative effects of FA on mental health problems such as agitation, anxiety, and irritability, using in vivo behavioral analysis, in vitro pharmacological analysis, and in silico binding analysis.

Methods

The effects of FA (10 mg/kg, 50 mg/kg, and 250 mg/kg) on hyperactivity and aggressive behaviors of isolation-reared mice were examined. The effects of FA (50 mg/kg and 250 mg/kg) on extracellular levels of monoamines such as serotonin (5-HT), dopamine, and noradrenaline were analyzed by in vivo microdialysis. The effects of FA (10⁻¹³–10⁻⁶ M) on 5-HT_1A and 5-HT_2A receptors were analyzed using a luciferase reporter gene assay. Binding of FA to the mouse 5-HT_1A receptor was evaluated by in silico analysis.

Results

The behavioral analysis showed that administration of FA (50 mg/kg) 1 h before experiments significantly alleviated hyperactivity and aggressive behaviors in isolation-reared mice. These alleviative effects were abolished by pretreatment with the 5-HT_1A receptor antagonist WAY-100635 (1 mg/kg). In vivo microdialysis analysis showed that FA (50 mg/kg) did not change extracellular monoamine levels in the prefrontal cortex of mice. The luciferase reporter gene assay indicated that FA activated 5-HT_1A receptors, but not 5-HT_2A receptors, in a dose-dependent manner. The maximal response of 5-HT_1A receptors to FA was weaker than that to 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), a 5-HT_1A receptor full agonist. In silico binding analysis showed that FA binds to the orthosteric site of 5-HT_1A receptors.

Conclusion

Taken together, these results suggest that FA ameliorates agitation-, anxiety-, and irritability-like behaviors such as hyperactivity and aggressive behaviors in isolation-reared mice via 5-HT_1A receptor partial agonist activity. These findings support the efficacy of FA on mental health problems that have been suggested in preclinical and clinical practice.

中文翻译：

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阿魏酸通过5-HT 1A受体部分激动剂活性减轻隔离饲养小鼠的异常行为

基本原理

临床前和临床报告表明，阿魏酸（FA）是一种植物来源的苯丙烷，对人类的精神健康问题有效，例如躁动，焦虑和烦躁不安，而不会引起不利的副作用。但是，作用机理尚不清楚。

客观的

该研究的目的是使用体内行为分析，体外药理学分析和计算机模拟结合分析来研究FA对精神健康问题如躁动，焦虑和易怒的改善作用的潜在机制。

方法

检查了FA（10 mg / kg，50 mg / kg和250 mg / kg）对孤立饲养的小鼠活动过度和攻击行为的影响。通过体内微透析分析了FA（50 mg / kg和250 mg / kg）对单胺如血清素（5-HT），多巴胺和去甲肾上腺素的细胞外水平的影响。使用荧光素酶报告基因分析法分析了FA（10 ^-13 –10 ^-6 M）对5-HT _1A和5-HT _2A受体的作用。通过计算机分析评估FA与小鼠5-HT _1A受体的结合。

结果

行为分析表明，实验前1小时施用FA（50 mg / kg）可以显着减轻隔离饲养小鼠的过度活跃和攻击行为。通过使用5-HT _1A受体拮抗剂WAY-100635（1 mg / kg）进行预处理，可以消除这些缓解作用。体内微透析分析表明，FA（50 mg / kg）不会改变小鼠前额叶皮层中的细胞外单胺水平。荧光素酶报告基因的测定表明，FA以剂量依赖的方式激活了5-HT _1A受体，但没有激活5 -HT _2A受体。的5-HT的最大应答_1A受体FA明显弱于至8-羟基-2-二丙氨基（8-OH-DPAT），5-HT _1A受体全激动剂。在计算机上的结合分析表明，FA与5-HT _1A受体的正构位点结合。

结论

综上所述，这些结果表明FA通过5-HT _1A受体部分激动剂活性改善了孤立饲养的小鼠中的激动，焦虑和易怒样行为，例如多动和攻击行为。这些发现支持了FA对临床前和临床实践中所建议的精神健康问题的功效。