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

Stop fear and anxiety

Opioid receptors activate either G proteins or β-arrestins. Many unwanted side effects associated with opioid use are mediated by β-arrestins. Therefore, drugs that bias opioid receptor signaling to G protein-mediated pathways are preferred for the treatment of pain. However, Ko et al. found that β-arrestin-biased drugs may have potential for treating fear and anxiety. Natural and synthetic opioids altered such behaviors in mice differently through specific signaling for G proteins and -arrestin in various regions of the brain that indicated distinct and compensatory functions of -arrestin isoforms. The results begin to reveal a context-specific aspect of opioid receptor signaling in neurological function and animal behavior.

Abstract

G protein coupled receptors (GPCRs) are involved in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways, but may also engage kinases and downstream effectors through β-arrestin-mediated scaffold interactions. Here, we investigated whether β-arrestin signaling regulates anxiety and fear-like behavior in mice in response to activation of the δ-opioid GPCR receptor (δOR or DOR). Administration of β-arrestin-biased δOR agonists to male C57BL / 6 mice revealed β-arrestin-2 dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2) in the hippocampus dorsal and amygdala-dependent and -arrestin 1 activation of ERK1 / 2 in the nucleus accumbens. In mice, treatment with the -arrestin agonist was associated with a reduction in anxiety and fear-related behaviors, with some overlap and isoform-specific entry. In contrast, application of a G protein-biased δOR agonist decreased ERK1 / 2 activity in all three regions as well as the dorsal striatum and was associated with an increase in fear-related behavior with no effects on basic anxiety. Our results indicate a complex picture of δOR neuromodulation in which β-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 results highlight the importance of non-canonical -arrestin-dependent GPCR signaling in the regulation of these interdependent emotions.

About Michael Bill

Check Also

Monteris Medical Announces Publication of Position Statements on Laser Interstitial Heat Therapy

PLYMOUTH, Minnesota., September 23, 2021 / PRNewswire / – Monteris Medical today announced that position …

Leave a Reply

Your email address will not be published. Required fields are marked *