Sex-specific Regulation of Fentanyl Reward by the Circadian Transcription Factor NPAS2

Abstract

Synthetic opioids like fentanyl are highly potent and prevalent in the illicit drug market, leading to tolerance, dependence, and opioid use disorder (OUD). Chronic opioid use disrupts sleep and circadian rhythms, which persist even during treatment and abstinence, increasing the risk of relapse. The body's molecular clock, regulated by transcriptional and translational feedback loops, controls various physiological processes, including the expression of endogenous opioids and their receptors. The circadian transcription factor NPAS2, highly expressed in the nucleus accumbens, may have a crucial role in opioid-related behaviors. Our study found a role for NPAS2 in fentanyl reward behaviors in male and female mice. NPAS2 also had sex-specific effects on fentanyl seeking and craving behaviors. We also identified specific cell types and transcriptional targets in the nucleus accumbens by which NPAS2 may mediate the impact of fentanyl on the brain and opioid reward-related behaviors.