(2R,6R)-hydroxynorketamine alleviates PTSD-like endophenotypes by regulating the PI3K/AKT signaling pathway in rats

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.

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.

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.

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.