Lithium and valproate act on the GSK-3β signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain

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...

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Published in:Neuropharmacology 2017-05, Vol.117, p.447-459
Main Authors: Valvassori, Samira S., Dal-Pont, Gustavo C., Resende, Wilson R., Jornada, Luciano K., Peterle, Bruna R., Machado, Alessandra Gonçalves, Farias, Hemelin Resende, de Souza, Claudio T., Carvalho, André F., Quevedo, João
Format: Article
Language:English
Subjects:
Animals
Antimanic Agents - pharmacology
AR-A014418
Bipolar disorder
Bipolar Disorder - drug therapy
Bipolar Disorder - enzymology
Disease Models, Animal
Frontal Lobe - drug effects
Frontal Lobe - enzymology
Glycogen Synthase Kinase 3 beta - antagonists & inhibitors
Glycogen Synthase Kinase 3 beta - metabolism
GSK-3β
Hippocampus - drug effects
Hippocampus - enzymology
Lithium
Lithium Compounds - pharmacology
Locomotion - drug effects
Locomotion - physiology
Male
Ouabain
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation - drug effects
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - metabolism
Rats, Wistar
Signal Transduction - drug effects
Thiazoles - pharmacology
Urea - analogs & derivatives
Urea - pharmacology
Valproate
Valproic Acid - pharmacology
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Summary: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. •Ouabain (OUA)-induced manic-like behavior in animal model of mania.•Mania is clinic march clinical of bipolar disorder; mood stabilizers such as lithium (Li) and valproate (VPA) reversed the manic-like behavior induced by OUA.•Bipolar patients overexpress GSK-3β; AR-A0144818, an inhibitor of GSK-3β, reversed the manic-like behavior induced by OUA.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2016.10.015