Exposure to anxiety- or fear-invoking stimuli initiate a convergence of executive actions orchestrated by multiple proteins and neurotransmitters across the brain. Dozens of G protein-coupled receptors (GPCRs) have been linked to regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but may also engage downstream kinases and effectors through β-arrestin scaffolds. Here, we investigate whether β-arrestin signaling is critical for the emotional regulation of

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... like and fear-related behavior. Using the δ-opioid receptor (δOR) as a model GPCR, we found that β-arrestin 2-dependent activation of extracellular signal-regulated kinases (ERK1/2) in the dorsal hippocampus and the amygdala are critical for δOR-induced anxiolytic-like effects. In contrast, G protein-mediated δOR signaling was associated with decreased ERK1/2 activity and increased fear-related behavior. Our results also suggest a potential contribution of β-arrestin 1 in fear-reducing effects. Overall, our findings highlight the significance of non-canonical β-arrestin signaling in the regulation of emotions.