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.