Pharmacology, biochemistry, and behavior · 2024
(2R,6R)-hydroxynorketamine alleviates PTSD-like endophenotypes by regulating the PI3K/AKT signaling pathway in rats.
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Liu Lifen, Li Rui, Wu Lanxia, Guan Yubo, Miao Miao, Wang Yuxuan, Li Changjiang, Wu Chunyan, Lu Guohua, Hu Xinyu, Sun Lin
Аннотация
BACKGROUND: Patients diagnosed with post-traumatic stress disorder (PTSD) mainly exhibit enduring adverse emotions, heightening susceptibility to suicidal thoughts and behaviors. Notably, metabolites of ketamine, particularly (2R,6R)-hydroxyketamine (HNK), have demonstrated favorable antidepressant properties. However, the precise mechanism through which HNK exerts its therapeutic effects on negative emotional symptoms in PTSD patients should be fully elucidated.
METHODS: In this investigation, a model involving a single prolonged stress and plantar shock (SPS&S) was utilized, followed by the administration of (2R, 6R)-HNK into the lateral ventricle subsequent to the recovery phase. The evaluation of PTSD-related behaviors was conducted through the open field test (OFT), elevated plus maze test (EMPT), and forced swim test (FST). The expression of phosphatidylinositol 3-kinase (PI3K)/phosphokinase B (AKT) signaling pathway in rat brain regions was analyzed using molecular biology experiments.
RESULTS: SPS&S rats displayed adverse emotional behaviors characterized by depression and anxiety. Treatment with (2R, 6R)-HNK enhanced exploratory behavior and reversed negative emotional behaviors. This intervention mitigated disruptions in the expression levels of PI3K/AKT signaling pathway-associated proteins in the HIP and PFC, without influencing PI3K/AKT signaling in the AMY of SPS&S rats.
CONCLUSION: Traumatic stress can trigger negative emotional reactions in rats, potentially involving the PI3K/AKT signaling pathway in the HIP, PFC, and AMY. The (2R, 6R)-HNK compounds have demonstrated the potential to mitigate adverse emotions in rats subjected to the SPS&S paradigm. This effect may be attributed to the modulation of the PI3K/AKT signaling pathway in the HIP, and PFC, with a particularly notable impact observed in the HIP region.
METHODS: In this investigation, a model involving a single prolonged stress and plantar shock (SPS&S) was utilized, followed by the administration of (2R, 6R)-HNK into the lateral ventricle subsequent to the recovery phase. The evaluation of PTSD-related behaviors was conducted through the open field test (OFT), elevated plus maze test (EMPT), and forced swim test (FST). The expression of phosphatidylinositol 3-kinase (PI3K)/phosphokinase B (AKT) signaling pathway in rat brain regions was analyzed using molecular biology experiments.
RESULTS: SPS&S rats displayed adverse emotional behaviors characterized by depression and anxiety. Treatment with (2R, 6R)-HNK enhanced exploratory behavior and reversed negative emotional behaviors. This intervention mitigated disruptions in the expression levels of PI3K/AKT signaling pathway-associated proteins in the HIP and PFC, without influencing PI3K/AKT signaling in the AMY of SPS&S rats.
CONCLUSION: Traumatic stress can trigger negative emotional reactions in rats, potentially involving the PI3K/AKT signaling pathway in the HIP, PFC, and AMY. The (2R, 6R)-HNK compounds have demonstrated the potential to mitigate adverse emotions in rats subjected to the SPS&S paradigm. This effect may be attributed to the modulation of the PI3K/AKT signaling pathway in the HIP, and PFC, with a particularly notable impact observed in the HIP region.