Aims: Mounting evidence suggests that bipolar disorder symptoms could be favorably influenced by modification of glycogen synthase kinase-3 (GSK3) activity. Specifically, the well known antimanic medications lithium, haloperidol, valproate and clozapine have been shown to inhibit GSK3 activity. GSK3 is phosphorylated and thus inhibited by protein kinase B (PKB) and serum and glucocorticoid inducible kinase (SGK) isoforms. The present study explored whether PKB/SGK dependent GSK3 regulation influences the behavior of mice. Methods: Gene targeted knockin mice with mutated and thus PKB/SGK resistant (gsk3KI) were compared to corresponding wild-type mice (gsk3WT). MicebaGSK3 were analysed by open field, LD-box, O-maze, emergence test, object exploration test and forced swim test. Body weight, food and fluid intake as well as levels of ACTH and corticosterone were determined. Results: Body weight was similar in both groups, whereas food and fluid intake were enhanced in gsk3KI. ACTH and cortisol levels were elevated in gsk3WT (265.03±39.0 vs. 124.5±29.3, p<0.01 and 356.29±74.74 vs. 187.74±39.15; p=0.078). In the open field, light-dark box and O-maze, gsk3KI mice showed a hyperactive and less anxious phenotype when compared to gsk3WT. Speed and distance of locomotion as well as rearings were significantly increased in gsk3KI. In the O-maze gsk3KI spent more time (16.96%±1.87 vs. 8.4%±1.81, p<0.01) and traveled a larger distance (4.13±0.42 vs. 1.66±0.52, p<0.01) in the open, unprotected area than gsk3WT indicating decreased anxiety and more risk assessment. Time of immobility in the forced swim test was decreased in gsk3KI mice (0.12 min±0.05 vs. 1.51 min±0.24, p<0.001) suggesting a less depressive phenotype. Conclusions: The present observations disclose a significant role of SGK/PKB-dependent regulation of GSK3 in the control of activity and anxiety. Accordingly, mice expressing SGK/PKB resistant GSK3 may be a valuable model of hyperactivity and mania.