Background:Depression is a heterogeneous disorder that affects a person?s mood, physical health and behavior. The present study aimed to investigate the potential antidepressant effect of adenosine triphosphate and cerebrolysin on reserpine induced depression in male rats through their effects on the levels of monoamine neurotransmitters and behavioral changes induced by reserpine. Material and methods: This study was conducted on 50 adult male rats divided into five groups: the first is the control group (C); the second depressed group received reserpine only. The third, fourth and fifth groups included depressed rats treated orally with citalopram as classical drug, ATP and cerebrolysin, respectively. Behavioral test, forced swim test, as well as brain neurotransmitters levels such as (MDA, 8OHdG, 5HT, DA, DOPAC, HVA, ATP and Na+-K+ ATPase) measured in brain tissue. Some biochemical parameters such as ALT, AST, TSH, T4 and testosterone were carried out in the serum. Results:Data showed that reserpine induced depressive-like behavior in the forced swim test. Additionally, reserpine produced a significant increase in the level of MAD, 8OHdG, DOPAC, HVA, T4, ALT and AST and significant decreased in 5-HT, DA, TSH, Testosterone, ATP and Na+-K+ ATPase as compared with control group. In contrast, cerebrolysin and ATP improve the behavioral parameters, decrease oxidative markers and increase neuronal function, liver function, and thyroid function and enhance testosterone level after 21 days of treatment in comparing with reserpine group and nearly to control group. Conclusion:Cerebrolysin has pronounced effect than ATP, citalopram and ameliorate reserpineinduced depression rats model.