It is known that bipolar disorder has a multifactorial etiology where the interaction between genetic and environmental factors are responsible for it development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzymes alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, from the eighth to the fourteenth days the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased Histone deacetylase and DNA methyltransferase activity in the animal’s brain. Valproate and sodium butyrate were able to reverse hyper locomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzymes activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between their selves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.This article is protected by copyright. All rights reserved.