β-Arrestin-dependent ERK signaling reduces anxiety-like and conditioned fear-related behaviors in mice

G protein-coupled receptors (GPCRs) are implicated in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but can also engage downstream kinases and effectors through scaffolding interactions mediated by beta-arrestin. Here, we investigated whether beta-arrestin signaling regulates anxiety-like and fear-related behavior in mice in response to activation of the GPCR delta-opioid receptor (delta OR or DOR). Administration of beta-arrestin-biased delta OR agonists to male C57BL/6 mice revealed beta-arrestin 2-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the dorsal hippocampus and amygdala and beta-arrestin 1-dependent activation of ERK1/2 in the nucleus accumbens. In mice, beta-arrestin-biased agonist treatment was associated with reduced anxiety-like and fear-related behaviors, with some overlapping and isoform-specific input. In contrast, applying a G protein-biased delta OR agonist decreased ERK1/2 activity in all three regions as well as the dorsal striatum and was associated with increased fear-related behavior without effects on baseline anxiety. Our results indicate a complex picture of delta OR neuromodulation in which beta-arrestin 1- and 2-dependent ERK signaling in specific brain subregions suppresses behaviors associated with anxiety and fear and opposes the effects of G protein-biased signaling. Overall, our findings highlight the importance of noncanonical beta-arrestin-dependent GPCR signaling in the regulation of these interrelated emotions.

Automated summary

In mice experiments, signaling through beta-arrestin was found to suppress anxiety and fear-related behaviors, while signaling through G proteins increased fear-related behavior. The results indicate a complex role of G protein-coupled receptors (GPCRs) in regulating anxiety and fear emotions.