Lithium and valproate act on GSK-3β signaling pathway to reverse the 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 PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, it was evaluated the effects of AR-A0144818, a GSK-3β inhibitor, on manic-like behaviour induced by OUA. 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-A0144818, or aCSF plus AR-A0144818. In the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed levels of p-PI3K, p-MAPK, p-Akt, p-GSK-3β in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased pPI3K, pAkt and pGSK-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-A0144818 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 on GSK-3β pathway. Show more