Nociceptin orphanin F/Q Pathways are dysregulated by stress and modulate reward responsiveness and motivated behavior across species.

Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has antidepressant/anti-anhedonic effects. However, the mechanisms underlying reward-related effects remain unclear. Here, we investigated the role of NOPR in a broad spectrum of reward-related phenotypes (reward consumption, reward learning, motivated behavior) alongside potentially prohedonic effects of NOPR antagonism across species. Study 1 evaluated whether exposure to early-life adversity upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. Study 2 assessed whether NOPR antagonism boosted reward learning in rats using the touchscreen-based Probabilistic Reward Task. Finally, Study 3 tested whether NOPR antagonism modulated decision about motivated behavior using the Effort Expenditure for Reward Task among depressed humans. In Study 1, early-life adversity induced reduced sucrose preference and produced enduring and sex-dependent alterations in effort-related reward behavior, and increased Pnoc expression in the VTA; in females (but not males), early-life adversity increased Pnoc expression in the dorsal striatum. In Study 2, acute administration of 30 mg/kg (but not lower doses) of a NOPR antagonist (BTRX-246040) enhanced reward learning in rats. Finally, in Study 3, relative to placebo, 8-week treatment with BTRX-246040 modulated choice consistency during a motivated task in depressed humans. Collectively, our findings indicate that chronic stress alters Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows promising efficacy in increasing reward-related behaviors in rodents and humans. Future studies using similar manipulations and outcome measures across species are warranted.