Depression is a pervasive mood disorder that continues to challenge researchers and clinicians worldwide. Caffeine and its derivatives have been studied for their neuroprotective and antidepressant effect. Current study aimed to explore the potential antidepressant effect of a caffeine derivative, Sy-2476 [4-(1, 3, 7-trimethyl-2, 6-dioxo-2, 3, 6, 7-tetrahydro-1H-purin-8-yl) benzo nitrile], in corticosterone-induced rat model of depression. Depression-like behaviour in rats was induced by administering 20 mg/kg hydrocortisone s.c for 21 days. Behavioural studies evaluated the potential antidepressant effect of caffeine derivative Sy-2476, its effect on cortisol levels, modulation of A1/A2receptors mRNA expression and antioxidant assays. Treatment of rats with Sy-2476 exhibited robust antidepressant-like effects in corticosterone-exposed rats by increasing sucrose preference (p = 0.0002) while reducing immobility time (p = 0.0118) in the forced swim test. Sy-2476 also reduced lipid peroxidation and increased the level of antioxidant enzymes, including glutathione, catalase, and superoxide dismutase. Moreover, Sy-2476 significantly lowered cortisol levels (p = 0.0019) and up-regulated mRNA expression of A1 (p = 0.0001) and A2receptors (p = 0.0016) compared to the corticosterone-only treated group. In conclusion, Sy-2476 showed an antidepressant effect primarily by suppressing serum cortisol levels, modulating the expression of adenosine receptors, and exhibiting antioxidant properties. A A
