Differential Effects of Cocaine and Morphine on the Diurnal Regulation of the Mouse Nucleus Accumbens Proteome

Substance use disorders are associated with disruptionsin sleepand circadian rhythms that persist during abstinence and may contributeto relapse risk. Repeated use of substances such as psychostimulantsand opioids may lead to significant alterations in molecular rhythmsin the nucleus accumbens (NAc), a brain region central to reward andmotivation. Previous studies have identified rhythm alterations inthe transcriptome of the NAc and other brain regions following theadministration of psychostimulants or opioids. However, little isknown about the impact of substance use on the diurnal rhythms ofthe proteome in the NAc. We used liquid chromatography coupled totandem mass spectrometry-based quantitative proteomics, along witha data-independent acquisition analysis pipeline, to investigate theeffects of cocaine or morphine administration on diurnal rhythms ofproteome in the mouse NAc. Overall, our data reveal cocaine and morphinedifferentially alter diurnal rhythms of the proteome in the NAc, withlargely independent differentially expressed proteins dependent ontime-of-day. Pathways enriched from cocaine altered protein rhythmswere primarily associated with glucocorticoid signaling and metabolism,whereas morphine was associated with neuroinflammation. Collectively,these findings are the first to characterize the diurnal regulationof the NAc proteome and demonstrate a novel relationship between thephase-dependent regulation of protein expression and the differentialeffects of cocaine and morphine on the NAc proteome. The proteomicsdata in this study are available via ProteomeXchange with identifierPXD042043.