Modulation of Circadian Glucocorticoid Oscillation via Adrenal Opioid-CXCR7 Signaling Alters Emotional Behavior

• Modulation of circadian glucocorticoid oscillation alters emotional behavior
• Circadian amplitude of glucocorticoid oscillation can be enhanced via CXCR7
• Proenkephalin A gene products act as endogenous ligands for CXCR7
• Activating the adrenal CXCR7-β-arrestin-MAPK pathway induces anxiolytic-like behavior

SummaryCirculating glucocorticoid levels oscillate with a robust circadian rhythm, yet the physiological relevance of this rhythmicity remains unclear. Here, we show that modulation of circadian glucocorticoid oscillation by enhancing its amplitude leads to anxiolytic-like behavior. We observed that mice with adrenal subcapsular cell hyperplasia (SCH), a common histological change in the adrenals, are less anxious than mice without SCH. This behavioral change was found to be dependent on the higher amplitude of glucocorticoid oscillation, although the total glucocorticoid secretion is not increased in these mice. Genetic and pharmacologic experiments demonstrated that intermediate opioid peptides secreted from SCH activate CXCR7, a β-arrestin-biased G-protein-coupled receptor (GPCR), to augment circadian oscillation of glucocorticoid levels in a paracrine manner. Furthermore, recapitulating this paracrine axis by subcutaneous administration of a synthetic CXCR7 ligand is sufficient to induce anxiolytic-like behavior. Adrenocortical β-arrestin-biased GPCR signaling is a potential target for modulating circadian glucocorticoid oscillation and emotional behavior.

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