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Objective Epigenetic modifications such as DNA methylation are known to participate in the development of depression in both human and animal models.However, the role of DNA methyltransferases (DNMTs) is less studied.The pyrimidine analogue zebularine inhibits DNA methylation by forming a covalent complex with DNMTs.Zebularine is a tumor cell proliferation suppressor and blocks the induction of long-term potentiation in mouse hippocampal slices.This experiment aimed to test the potent antidepressant-like effect of zebularine using the behavioral despair model of forced swimming test.Methods Lateral ventricle carmulation (AlP-0.8 mm, M/L +0.6 mm, D/V-4.1 mm from bregrna) was performed on male SD rats (n =36) 7 d prior to experiment.Acute forced swimming test in the rat contained 2 sessions separated by 24 h, a habituation session of 15 min which ensures a stable duration of immobility, and a test session of 5 min.Zebularine was infused intracerebroventricularly (i.c.v.) 24 h, 120 min and 15 min before the test session at the dose of 0.3 μg, 0.6 μg, 1.2 tg in 2 tL 0.9% sterile saline containing 10% DMSO.The control group received vehicle infusion.The duration of climbing and floating time is recorded.Results Infusion of zebularine (i.c.v.) significantly increased climbing time [F(3,32) =6.721, P < 0.01) and reduced floating time [F(3,32) =3.286, P < 0.05) in the acute forced swimming test.Post-hoc analysis showed that the 1.2 μg dose of zebularine increased climbing behavior (P < 0.01), and zebularine reduced the time of immobility at the doses of 0.6 μg (P < 0.05) and 1.2 μg (P < 0.05), all compared to vehicle infusion.Conclusion Acute administration ofzebularine has an antidepressant-like effect in rats.