Creatine prevents ouabain-induced manic-like behavior by modulating GSK-3β via PI3K/AKT/mTOR pathway

Bipolar disorder is a chronic psychiatric condition marked by alternating episodes of mania and depression. Current pharmacological treatments show limited efficacy and are often associated with incomplete remission. Creatine, a compound involved in energy buffering, mitochondrial function, and neuromodulation, has demonstrated neuroprotective and potential mood-stabilizing properties. However, the underlying mechanisms remain poorly understood. This study evaluated the effects of acute oral creatine administration (300 mg/kg) on behavioral and molecular changes in a validated rat model of mania induced by intracerebroventricular ouabain (10^-3 M), a Na⁺/K⁺-ATPase inhibitor. Behavioral alterations were assessed using the open field test, and hippocampal samples were analyzed for enzyme activity and key signaling proteins. Creatine significantly attenuated ouabain-induced hyperactivity and increased latency to symptom onset. At the molecular level, creatine preserved Na⁺/K⁺-ATPase activity and reduced phosphorylation of its α-subunit at a regulatory site. Additionally, creatine enhanced activation of the PI3K/AKT/mTOR/p70S6K pathway and prevented the ouabain-induced activation of GSK-3β, a kinase involved in mood regulation. Notably, rapamycin, an mTOR inhibitor, reversed the behavioral effects of creatine, suggesting a mechanistic role for this pathway. These findings demonstrate that acute creatine administration confers both behavioral and neurochemical protection in a mania model and supports its potential as an adjunctive therapeutic strategy for individuals with bipolar disorder.