Acute ethanol (EtOH) consumption exerts a biphasic effect on behavior and increases serotonin levels in the brain. However, the molecular mechanisms underlying alcohol-mediated behavioral responses still remain to be fully elucidated. Here, we investigate pharmacologically the involvement of the serotonergic pathway on acute EtOH-induced behavioral changes in zebrafish. We exposed zebrafish to 0.25, 0.5, 1.0% (v/v) EtOH for 1 h and analyzed the effects on aggression, anxiety-like behaviors, and locomotion. EtOH concentrations that changed behavioral responses were selected to the subsequent experiments. As a pharmacological approach, we used pCPA (inhibitor of tryptophan hydroxylase), WAY100135 (5-HT1A antagonist), buspirone (5-HT1A agonist), CGS12066A and CGS12066B (5-HT1B antagonist and agonist, respectively), ketanserin (5-HT2A antagonist) and (±)-DOI hydrochloride (5-HT2A agonist). All serotonergic receptors tested modulated aggression, with a key role of 5-HT2A in aggressive behavior following 0.25% EtOH exposure. Because CGS12066B mimicked 0.5% EtOH anxiolysis, which was antagonized by CGS12066A, we hypothesized that anxiolytic-like responses are possibly mediated by 5-HT1B receptors. Conversely, the depressant effects of EtOH are probably not related with direct changes on serotonergic pathway. Overall, our novel findings demonstrate a role of the serotonergic system in modulating the behavioral effects of EtOH in zebrafish. These data also reinforce the growing utility of zebrafish models in alcohol research and help elucidate the neurobiological mechanisms underlying alcohol abuse and associated complex behavioral phenotypes.

中文翻译：

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血清素系统在乙醇诱导的攻击和焦虑中的作用：使用斑马鱼模型的药理学方法

急性乙醇 (EtOH) 消耗对行为产生双相效应并增加大脑中的血清素水平。然而，酒精介导的行为反应的分子机制仍有待充分阐明。在这里，我们从药理学上研究了血清素通路对斑马鱼急性乙醇诱导的行为变化的影响。我们将斑马鱼暴露于 0.25、0.5、1.0% (v/v) 乙醇中 1 小时，并分析其对攻击性、焦虑样行为和运动的影响。选择改变行为反应的 EtOH 浓度用于后续实验。作为药理学方法，我们使用 pCPA（色氨酸羟化酶抑制剂）、WAY100135（5-HT1A 拮抗剂）、丁螺环酮（5-HT1A 激动剂）、CGS12066A 和 CGS12066B（分别为 5-HT1B 拮抗剂和激动剂），ketanserin（5-HT2A 拮抗剂）和 (±)-DOI 盐酸盐（5-HT2A 激动剂）。测试的所有血清素能受体都调节了攻击性，5-HT2A 在 0.25% EtOH 暴露后的攻击性行为中起关键作用。因为 CGS12066B 模拟了 0.5% EtOH 抗焦虑，它被 CGS12066A 拮抗，我们假设抗焦虑样反应可能是由 5-HT1B 受体介导的。相反，EtOH 的抑制作用可能与 5-羟色胺能通路的直接变化无关。总体而言，我们的新发现证明了血清素能系统在调节 EtOH 对斑马鱼的行为影响方面的作用。这些数据还加强了斑马鱼模型在酒精研究中日益增长的效用，并有助于阐明酒精滥用和相关复杂行为表型的神经生物学机制。