Dissecting the roles of ß-arrestin2 and GSK-3 signaling in 5-HT1BR-mediated perseverative behavior and prepulse inhibition deficits in mice.
PLoS One
; 14(2): e0211239, 2019.
Article
em En
| MEDLINE
| ID: mdl-30721232
ABSTRACT
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-3ß, and a noncanonical pathway mediated by the adaptor protein ß-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 ß-arrestin2 inhibition in treatment of perseverative behaviors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Quinase 3 da Glicogênio Sintase
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Receptor 5-HT1B de Serotonina
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Inibição Pré-Pulso
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Beta-Arrestina 2
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Locomoção
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article