Accumulating evidence has suggested the possible involvement of sodium and potassium-activated adenosine triphosphatase (Na-K ATPase) dysfunction in the pathophysiology of bipolar disorder. According to this hypothesis, pharmacological rat model for mania using intracerebroventricular (ICV) injection of ouabain, a specific Na-K ATPase inhibitor, has been proposed. However, the molecular mechanisms related to the oubain-induced behavioral changes still remain to be elucidated. Beyond the traditionally known role of Na-K ATPase as an ion-transporting pump, recent research shows that ouabain acts as a ligand for Na-K ATPase and induces signal transduction in intracellular signaling pathways. We have investigated the involvement of intracellular signal transduction mechanisms in ouabain rat model for mania. ICV treatment of ouabain induced changes in ERK1/2, Akt, and PKC related signal pathways in rat brain related to alterations in locomotor activity. These signal changes induced activation of protein translation initiation pathways and protein synthesis rate, expression of immediate early genes, and changes in the activity of transcription factors related to cell survival and apoptosis in rat brain. In addition, ouabain-induced changes in behaviors and signal pathways were affected by treatment of antipsychotics, a calcium channel blocker, and a selective MEK1/2 inhibitor. These findings could provide insight for the molecular mechanisms of bipolar disorder linking ion pump dysfunctions and altered intracellular signaling.