Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
Committee on Neurobiology, University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2019 Feb 5;14(2):e0211239. doi: 10.1371/journal.pone.0211239. eCollection 2019.
Serotonin-1B receptors (5-HT1BRs) modulate perseverative behaviors and prepulse inhibition (PPI) in humans and mice. These inhibitory G-protein-coupled receptors signal through a canonical G-protein-coupled pathway that is modulated by GSK-3β, and a noncanonical pathway mediated by the adaptor protein β-arrestin2 (Arrb2). Given the development of biased ligands that differentially affect canonical versus noncanonical signaling, we examined which signaling pathway mediates 5-HT1BR agonist-induced locomotor perseveration and PPI deficits, behavioral phenotypes observed in both obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD). To assess the role of canonical 5-HT1BR signaling, mice received acute pretreatment with a GSK-3 inhibitor (SB216763 or AR-A014418) and acute treatment with the 5-HT1A/1B receptor agonist RU24969 prior to assessing perseverative locomotor behavior in the open field, and PPI. To determine the role of noncanonical 5-HT1BR signaling, Arrb2 wild-type (WT), heterozygous (HT), and knockout (KO) mice received acute RU24969 treatment prior to behavioral testing. GSK-3 inhibition increased locomotor perseveration overall, and also failed to influence the RU24969-induced perseverative locomotor pattern in the open field. Yet, GSK-3 inhibition modestly reduced RU24969-induced PPI deficits. On the other hand, Arrb2 HT and KO mice showed reduced locomotion and no changes in perseveration overall, in addition to modest reductions in RU24969-induced locomotion and PPI deficits. In conclusion, our data do not support use of either GSK-3 inhibitors or β-arrestin2 inhibition in treatment of perseverative behaviors.
5-羟色胺 1B 受体（5-HT1BR）调节人类和小鼠的持续行为和前脉冲抑制（PPI）。这些抑制性 G 蛋白偶联受体通过 GSK-3β 调节的经典 G 蛋白偶联途径和由衔接蛋白β-arrestin2（Arrb2）介导的非经典途径信号转导。鉴于偏倚配体的发展，这些配体对经典途径与非经典途径的信号转导有不同的影响，我们研究了哪种信号转导途径介导了 5-HT1BR 激动剂诱导的运动性持续行为和 PPI 缺陷，这些行为表型在强迫症（OCD）和自闭症谱系障碍（ASD）中均有观察到。为了评估经典 5-HT1BR 信号转导的作用，小鼠接受了 GSK-3 抑制剂（SB216763 或 AR-A014418）的急性预处理，然后用 5-HT1A/1B 受体激动剂 RU24969 急性处理，然后在旷场中评估持续运动行为，以及 PPI。为了确定非经典 5-HT1BR 信号转导的作用，Arrb2 野生型（WT）、杂合型（HT）和敲除（KO）小鼠在行为测试前接受急性 RU24969 处理。GSK-3 抑制总体上增加了运动性持续行为，并且也未能影响 RU24969 在旷场中诱导的持续运动模式。然而，GSK-3 抑制适度降低了 RU24969 诱导的 PPI 缺陷。另一方面，Arrb2 HT 和 KO 小鼠表现出运动减少和总体上无持续行为变化，此外，RU24969 诱导的运动和 PPI 缺陷也适度减少。总之，我们的数据不支持使用 GSK-3 抑制剂或β-arrestin2 抑制剂治疗持续行为。
