title: Lithium and valproate act on the GSK-3β signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain.
abstract: The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3β inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3β in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3β levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3β, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3β pathway.
authors: Laboratory of Neuronal Signaling and Psychopharmacology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil. Electronic address: samiravalvassori@unesc.net.
authors: Samira S
authors: SS
authors: Valvassori
authors: Laboratory of Neuronal Signaling and Psychopharmacology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Gustavo C
authors: GC
authors: Dal-Pont
authors: Laboratory of Neuronal Signaling and Psychopharmacology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Wilson R
authors: WR
authors: Resende
authors: Laboratory of Neuronal Signaling and Psychopharmacology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Luciano K
authors: LK
authors: Jornada
authors: Laboratory of Neuronal Signaling and Psychopharmacology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Bruna R
authors: BR
authors: Peterle
authors: Laboratory of Exercise Biochemistry and Physiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Alessandra Gonçalves
authors: AG
authors: Machado
authors: Laboratory of Exercise Biochemistry and Physiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Hemelin Resende
authors: HR
authors: Farias
authors: Laboratory of Exercise Biochemistry and Physiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
authors: Claudio T
authors: CT
authors: de Souza
authors: Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: André F
authors: AF
authors: Carvalho
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil; Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, TX, USA; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, TX, USA; Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors: João
authors: J
authors: Quevedo
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D018020:Lithium Compounds / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D010042:Ouabain; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D010042:Ouabain; D014635:Valproic Acid; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: AR-A014418; Bipolar disorder; GSK-3β; Lithium; Ouabain; Valproate