〔Abstract〕 Objective To explore the effects of acute sleep deprivation on manic-like behavior in mice and its possible molecular mechanisms. Methods Seventy-three 8-week male C57BL/6 mice were randomly divided into two groups: control group(ctrl group,n=36) and acute sleep deprivation group(SD group,n=37). After acute sleep deprivation, the motor and exploration ability of mice were evaluated by open field test and elevated plus maze. Depression-like behavior of mice was evaluated by tail suspension test. Neuronal activation in brain tissue was observed by c-fos staining, neurotransmitter levels in hippocampus(HIP) and medial prefrontal cortex(mPFC) were detected by ELISA Kit, and glycogen synthase kinase-3β(GSK-3β) and phosphorylated GSK-3β(p-GSK-3β) levels in HIP and mPFC were detected by Western blot. Results Compared with the ctrl group, the total movement distance(P<0.05) and the time in the central area(P<0.05) of the mice in SD group significantly increased in the open field test, and the open arm time(P<0.000 1) and open arm distance(P<0.01) significantly increased in the elevated plus maze. In the tail suspension test, the immobility time(P<0.01) was significantly reduced. In SD group, the expression of c-fos in HIP and mPFC increased(P<0.01), and the level of neurotransmitter DA in HIP(P<0.05) and mPFC(P<0.01) significantly increased. Western blot results showed that compared with ctrl group, the ratio of p-GSK-3β and GSK-3β in mPFC and HIP significantly decreased in SD group(P<0.000 1,P<0.05), while the level of p-GSK-3β protein significantly decreased in mPFC(P<0.05), but there was no significant change in HIP. Conclusion Acute sleep deprivation may regulate the level of GSK-3 through DA in mPFC of mice, inhibiting the serine phosphorylation of GSK-3 and eventually leading to manic-like behavior in mice.