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

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.

Towards a Natural Treatment for Mania: Red Onion Husk Extract Modulates Neuronal Resilience, Redox Signalling, and Glial Activation.

“…This study explores the potential of the avonoid-rich fraction (FRF) of onion husk extract in preventing BD progression using a ketamine-induced hyperlocomotion model in rats. Ketamine, an NMDA receptor antagonist, mimics manic-like behavior in rodents, replicating some key features of BD episodes (Ni et al, 2022).…”

Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor PLX3397

“…The specificity of the primary rabbit anti-Iba1 antibody (#019-19,741, Wako, Osaka, Japan; RRID: AB_839504) was tested extensively (Brett et al, 2022;Zhang et al, 2018). The experimental procedure was performed as previously described with some modifications (Gao et al, 2021;Ni et al, 2022). First, the sections were washed with PBS for 30 min on a shaker to remove the cryoprotectant solution.…”