-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.


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.

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