In this study we investigated the effects of Sodium Butyrate (SB, a histone deacetilase inhibitor) and Tamoxifen (TMX, a protein kinase C inhibitor) on creatine kinase (CK) activity in rats submitted to an animal model of mania. In the reversal treatment, amphetamine (AMPH) or saline was administered to rats for 14 days, and between days 8-14, rats were treated with SB, TMX or saline. In the prevention treatment, rats were pretreated with SB, TMX or saline, and between days 8-14, AMPH or saline were administrated. In both experiments, locomotor activity was assessed by open-field test and CK activity in amygdala, prefrontal, hippocampus and striatum. Our results showed that SB and TMX reversed and prevent AMPH-induced behavioral effects. Moreover, AMPH (reversal treatment) inhibited CK activity in hippocampus and striatum, but not in amygdala and prefrontal, and administration of SB and TMX did not reverse the enzyme inhibition. In the prevention treatment, AMPH decreased CK activity in saline-pretreated rats in amygdala, hippocampus and striatum. AMPH administration in SB or TMX-pretreated animals decreased CK activity in amygdala and hippocampus. These findings showed that SB and TMX reversed and prevented AMPH-induced behavioral effects; AMPH inhibited CK activity and SB and TMX were not able to reverse and/or prevent the enzyme inhibition. These findings reinforce the hypothesis that PKC and HDAC play an important role in the pathophysiology of bipolar disorder, but nor TMX neither SB were able to reverse and prevent the change in CK activity induced by AMPH.