Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Chronic lithium exposure reduces mania-like behavior and c-Fos expression in the medial prefrontal cortex of adult male mice treated with ketamine. Transcriptome sequencing of the prefrontal cortex shows that lithium inactivates the PI3K-AKT signaling pathway. Inhibiting AKT signaling with MK2206 or knocking down AKT in the mPFC reverses ketamine-induced mania, while activating AKT with SC79 promotes mania in low-dose ketamine-treated mice. Inhibiting PI3K with LY294002 also reverses mania, but inhibiting mTOR with rapamycin has no effect. Lithium may therefore ameliorate ketamine-induced mania via the PI3K-AKT pathway, suggesting a novel target for bipolar disorder treatment.

Study at a glance

Abstract

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.