title: Endogenous cardiac steroids in animal models of mania.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hodes
authors.affiliation: Departments of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Deutsch
authors.affiliation: Department of Psychiatry, Hadassah Hospital, Jerusalem, Israel.
authors.forename: Tzuri
authors.initials: T
authors.lastname: Lifschytz
authors.affiliation: School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Tel-Aviv, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Einat
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Lichtstein
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001714:Bipolar Disorder / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005625:Frontal Lobe / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010042:Ouabain / Q000276:immunology*; D010766:Phosphorylation / Q000502:physiology
chemical_list: D000906:Antibodies; D010042:Ouabain
keywords: Na+, K+-ATPase; animal behavior; endogenous cardiac steroids; mania; ouabain