title: Histone deacetylase inhibitors reverse manic-like behaviors and protect the rat brain from energetic metabolic alterations induced by ouabain.
abstract: Studies have revealed alterations in mitochondrial complexes in the brains of bipolar patients. However, few studies have examined changes in the enzymes of the tricarboxylic acid cycle. Several preclinical studies have suggested that histone deacetylase inhibitors may have antimanic effects. The present study aims to investigate the effects of lithium, valproate and sodium butyrate, a histone deacetylase inhibitor, on the activity of tricarboxylic acid cycle enzymes in the brains of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single intracerebroventricular injection of ouabain or cerebrospinal fluid. Starting on the day following the intracerebroventricular injection, the rats were treated for 7days with intraperitoneal injections of saline, lithium, valproate or sodium butyrate. Risk-taking behavior, locomotor and exploratory activities were measured using the open-field test. Citrate synthase, succinate dehydrogenase, and malate dehydrogenase were examined in the frontal cortex and hippocampus. All treatments reversed ouabain-related risk-taking behavior and hyperactivity in the open-field test. Ouabain inhibited tricarboxylic acid cycle enzymes in the brain, and valproate and sodium butyrate but not lithium reversed this ouabain-induced dysfunction. Thus, protecting the tricarboxylic acid cycle may contribute to the therapeutic effects of histone deacetylase inhibitors.
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Jéssica
authors.initials: J
authors.lastname: Lopes-Borges
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil. Electronic address: samiravalvassori@unesc.net.
authors.forename: Samira S
authors.initials: SS
authors.lastname: Valvassori
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Varela
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Paula T
authors.initials: PT
authors.lastname: Tonin
authors.affiliation: Laboratory of Bioenergetics, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Vieira
authors.affiliation: Laboratory of Bioenergetics, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Cinara L
authors.initials: CL
authors.lastname: Gonçalves
authors.affiliation: Laboratory of Bioenergetics, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil.
authors.forename: Emilio L
authors.initials: EL
authors.lastname: Streck
authors.affiliation: Laboratory of Neurosciences, National Institute for Translational Medicine (INCT-TM), Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC 88806-000, Brazil; Center for Experimental Models in Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D020148:Butyric Acid / Q000494:pharmacology; D002952:Citric Acid Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010042:Ouabain / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018692:Antimanic Agents; D056572:Histone Deacetylase Inhibitors; D020148:Butyric Acid; D010042:Ouabain; D014635:Valproic Acid; D008094:Lithium
keywords: Bipolar disorder; Histone deacetylases; Tricarboxylic acid cycle