No 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.

Background: Mice with a deletion at exon 19 of the circadian locomotor output cycles Kaput gene (Clock delta19) exhibit mania-like behavior and have been one of the most common animal models for bipolar disorder (BD). The predictive validity of the Clock delta19 was investigated via studies using lithium previously. Determination of effects of other mood stabilizers on Clock delta19 mouse would be helpful for better understanding of the mechanism underlined. Methods: Wildtype (WT) and Clock delta19 mice were treated with saline (n = 10 for WT and n=10 for Clock delta19) or valproate (VPA) (n = 10 for WT and n=10 for Clock delta19) for 10 days. The hyperactivity, anxiety-like behaviors and depression-like behaviors were tested. The concentration of monoamine neurotransmitters and their metabolites in the hippocampus of saline or VPA treated WT and Clock delta19 mouse (n = 8 for each) were also determined. Results: VPA can reverse hyperactivity, lower level of anxiety-like and depression-like behaviors of the Clock delta19 mouse. Clock delta19 mouse exhibited lower levels of serotonin (5-HT) and dopamine (DA) in right hippocampus compared to WT mouse. Chronic VPA treatment did not affect the levels of 5-HT and DA, but can reduce the level of levodopa (L-DOPA) in the right hippocampus of Clock delta19 mouse. Conclusion: Our results indicated that chronic VPA treatment can reverse the mania-like behaviors of the Clock delta19 mouse and further consolidate the validity of the Clock delta19 mouse as a model of BD. Monoamine neurotransmitters and their metabolites in the hippocampus are partly regulated by mutation of the Clock gene or VPA treatment.