Endogenous cardiac steroids in animal models of mania

Objectives: Bipolar disorder (BD) is a complex psychiatric disorder characterized by mania and depression. Alterations in brain Na⁺, K⁺-ATPase and cardiac steroids (CSs) have been detected in BD, raising the hypothesis of their involvement in this pathology. The present study investigated the behavioral and biochemical consequences of a reduction in endogenous brain CS activity in animal models of mania. Methods: Amphetamine (AMPH)-induced hyperactivity in BALB/c and black Swiss mice served as a model of mania. Behavior was evaluated in the open-field test in naïve mice or in mice treated with anti-ouabain antibodies. CS levels were determined by enzyme-linked immunosorbent assay (ELISA), using sensitive and specific anti-ouabain antibodies. Extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) phosphorylation levels in the frontal cortex were determined by western blot analysis. Results: Administration of AMPH to BALB/c and black Swiss mice resulted in a marked increase in locomotor activity, accompanied by a threefold increase in brain CSs. The lowering of brain CSs by the administration of anti-ouabain antibodies prevented the hyperactivity and the increase in brain CS levels. AMPH caused an increase in phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt) levels in the frontal cortex, which was significantly reduced by administration of the antibodies. A synthetic ‘functional antagonist’ of CSs, 4-(3′α-15′β-dihydroxy-5′β-estran-17′β-yl) furan-2-methyl alcohol, also resulted in attenuation of AMPH-induced hyperactivity. Conclusions: These results are in accordance with the notion that malfunctioning of the Na⁺, K⁺-ATPase/CS system may be involved in the manifestation of mania and identify this system as a potential new target for drug development.