Role of Adenosine Receptors in Sleep Deprivation-Induced Depression-Like Behaviors

Sleep deprivation (SD) disrupts homeostatic regulation and increases vulnerability to stress and mood disorders.This study investigated the duration-dependent effects of SD and elucidated the distinct roles of adenosine A1 receptors (A1R) and A2A receptors (A2AR) in behavioral and molecular alterations induced by 24, 48, and 72 h of SD in mice.SD for 48 h and 72 h, but not 24 h, significantly increased immobility time in the tail suspension test (TST) and forced swim test (FST), accompanied by elevated plasma corticosterone (CORT) levels, indicating a duration-dependent stress response.Hippocampal A1R mRNA expression was significantly reduced, whereas A2AR mRNA expression was markedly increased at 48 h and 72 h of SD.Pharmacological blockade of either A1R (DPCPX) or A2AR (SCH 58261) significantly attenuated SD-induced depression-like behaviors and CORT elevation, whereas activation of A1R with the agonist CPA exacerbated depression-like behavior at 24 h and 48 h of SD.These findings suggest that A2AR upregulation may represent a pathological response to prolonged SD, whereas A1R downregulation may reflect compensatory adaptation to sustained receptor activation.Taken together, our results demonstrate that A1R and A2AR play distinct roles in SD-induced depression-like behaviors.