Accumulating evidence has pointed to the direct inhibitory action of lithium, an anti-depressant, on GSK-3 beta. The present study investigated further insight into lithium signaling pathways. In the cell-free assay Li2CO3 significantly inhibited phosphoinositide 3-kinase (PI3K)-mediated phosphorylation of Akt1 at Ser473, but Li2CO3 did not affect PI3K-mediated PI(3,4,5)P-3 production and 3-phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation of Akt1 at Thr308. This indicates that lithium could enhance GSK-3 beta activity by suppressing Akt-mediated Ser9 phosphorylation of GSK-3 beta in association with inhibition of PI3K-mediated Akt activation. There was no direct effect of Li2CO3 on Akt1-induced phosphorylation of GSK-3 beta at Ser9, but otherwise Li2CO3 significantly reduced GSK-3 beta-mediated phosphorylation of beta-catenin at Ser33/37 and Thr41. This indicates that lithium directly inhibits GSK-3 beta in an Akt-independent manner. In rat hippocampal slices Li2CO3 significantly inhibited phosphorylation of Akt1/2 at Ser473/474, GSK-3 beta at Ser9, and beta-catenin at Ser33/37 and Thr41. Taken together, these results indicate that lithium exerts its potentiating and inhibiting bidirectional actions on GSK-3 beta activity. (C) 2014 Elsevier Inc. All rights reserved.