Abstract The aim of the present study is to investigate the role of pro- and anti-inflammatory cytokines in the modulation of the neurotransmitter system in the rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes if IL-1β-associated changes in peripheral inflammatory pathways. Prostaglandin E (PGE2), or corticosterone (CORT) are associated with depressive like behaviors; and the effect of IL-4 on the neurotransmitter system in the CNS, concentration of serotonin (5-HT) and norepinephrine (NE) were examined after IL-1β intracerebroventricular (i.c.v.) injection. In the present study, IL-4 treatment (100ng and 200ng) significantly decreased anhedonic response and increased social exploration and total activity. Also, infusion of the IL-4 intracerebroventricular (i.c.v) markedly decreased IL-1β-induced PGE2 and CORT and also influenced 5-HT and NE synthesis, which might contribute to the behavioral changes elicited by IL-1β. IL-4 is likely to play a role in mediating behavioral consequences by regulating 5-HT and NE monoamines synthesis. In summary, excess pro-inflammation may play a role in the development of depressive behavior, and IL-4 is an important link between the changes in hormonal and neurotransmitter systems that are of recognized relevance for IL-1β-induced depressive responses. Also, the present findings contribute another significant piece of the puzzle and can be used as an important guiding rubric for those who seek to understand the relationship between depression and neuroinflammation by regulating neurotransmitter metabolism.