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.
氯胺酮是一种快速起效的抗抑郁药，已被用于治疗重度抑郁症和双相情感障碍。最近的研究表明氯胺酮可能会诱发用药患者出现躁狂症的风险。氯胺酮已用于建立躁狂症动物模型。然而，其机制仍不清楚。在该研究中，我们发现慢性锂暴露可减弱氯胺酮诱导的成年小鼠躁狂样行为和内侧前额叶皮层（mPFC）中c-Fos的表达。此外，转录组测序分析探究锂治疗对氯胺酮诱导的小鼠前额叶皮层转录组的影响，确定了磷酸肌醇3-激酶（PI3K）-蛋白激酶B（AKT）信号通路的失活参与了此过程。进一步，选择性AKT抑制剂MK2206可逆转氯胺酮诱导的躁狂样行为。通过AAV选择性敲低mPFC中的AKT也可逆转氯胺酮诱导的躁狂样行为。更重要的是，AKT激活剂SC79可使低剂量氯胺酮处理的小鼠出现躁狂样行为。同样地，PI3K抑制剂LY294002也可逆转氯胺酮诱导的小鼠躁狂样行为。但是，mTOR抑制剂雷帕霉素不能改善氯胺酮诱导的躁狂样行为。总之，我们的结果表明慢性锂治疗通过PI3K-AKT信号通路改善氯胺酮诱导的躁狂样行为。PI3K-AKT信号通路有可能发展为双相情感障碍治疗的新靶点。.
Keywords: Bipolar disorder; Ketamine; Lithium; Manic; Medial prefrontal cortex; PI3K-AKT signaling pathway.