Research Article: Dissecting the roles of β-arrestin2 and GSK-3 signaling in 5-HT1BR-mediated perseverative behavior and prepulse inhibition deficits in mice

Date Published: February 5, 2019

Publisher: Public Library of Science

Author(s): Summer L. Thompson, Stephanie C. Dulawa, Efthimios M. C. Skoulakis.


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.

Partial Text

Serotonin-1B receptors (5-HT1BRs), previously termed 5-HT1Dβ in humans [1], modulate perseverative behavior and prepulse inhibition (PPI) in humans [2–5] and mice [6–9]. Perseverative behavior refers to the inappropriate and inflexible repetition of a behavior, while PPI is a form of plasticity of the startle reflex that is thought to quantify sensorimotor gating, the ability to filter out extraneous sensory, cognitive, and motor information [10]. Perseverative behavior and deficient PPI are features of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) [11]. Some evidence suggests that perseverative behavior and PPI levels may be correlated [12,13]. Currently, chronic treatment with serotonin reuptake inhibitors (SRIs) provides the only pharmacological monotherapy for treating perseverative symptoms in OCD and ASD [14–16]. Thus, novel treatments for these disorders represent a major unmet need.

Our present findings show that both GSK-3 inhibition and Arrb2 knockout modestly reduce 5-HT1BR-induced PPI deficits, but do not diminish 5-HT1BR-induced locomotor perseveration. Specifically, neither GSK-3 inhibition nor Arrb2 knockout altered RU24969-induced reductions in spatial d or rearing behavior. Arrb2 knockout was found to reduce 5-HT1BR-induced hyperactivity, which reflects the amount but not the perseverative quality of locomotion, while GSK-3 inhibition had no effect on RU24969-induced hyperactivity. Thus, both canonical and noncanonical 5-HT1BR signaling plays a modest role in RU24969-induced PPI deficits, but not 5-HT1BR-induced perseverative behavior. Overall, our findings do not support a role for 5-HT1BR antagonists biased toward canonical or β-arrestin2-mediated signaling pathways as therapeutics for perseverative or compulsive behaviors.




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