Acute Sleep Deprivation in Adolescence Produces Transcriptional Changes in the Orexin System and Regulates Motivation for Reward.

Background: Acute sleep loss has been linked to increased reward-seeking behaviors in both humans and animals, including increased food consumption, greater risk taking for reward, and increased substance use in previous substance users. During adolescence, developing reward systems are already particularly vulnerable to substance use. Therefore, any acute sleep loss that occurs during adolescence may further heighten reward-seeking behaviors, increasing susceptibility to substance misuse and substance use disorder. Methods: Male and female heterogeneous stock rats underwent a 6-hour acute sleep deprivation session prior to testing motivation for a sucrose pellet reward under a progressive ratio schedule or transcriptomic analysis of nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) gene expression relative to control sleep. Results: Rats of both sexes exhibited increased motivation for sucrose reward for at least 3 days following sleep deprivation and substantial changes in gene transcription that were largely conserved across brain regions, although the mPFC showed more transcriptional changes than the NAc. Pathway analyses indicated major changes related to cellular development, immune signaling, and rhythmic processes. The orexin system, particularly the orexin 2 receptor (OX2R), was strongly upregulated in the mPFC and NAc, so we determined the effect of the OX2R antagonist seltorexant (10 mg/kg) on sleep deprivation-induced motivation for reward and found that seltorexant acutely reduced responding for sucrose under both sleep deprivation and sleep recovery conditions. Conclusions: These results suggest that acute sleep deprivation induces profound changes in the reward system and cellular function in adolescents, including the orexin system, that may modulate motivation for reward.