(2R,6R)-hydroxynorketamine alleviates PTSD-like endophenotypes by regulating the PI3K/AKT signaling pathway in rats.
Lifen Liu, Rui Li, Lanxia Wu, Yubo Guan, Miao Miao, Yuxuan Wang, Changjiang Li, Chunyan Wu, Guohua Lu, Xinyu Hu, Lin Sun
Pharmacology, biochemistry, and behavior December 1, 2024 DOI: 10.1016/j.pbb.2024.173891 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Rats subjected to single prolonged stress and plantar shock (SPS&S) |
| Interventions | (2R 6R)-hydroxyketamine (HNK) |
| Topics | PTSD Ketamine |
| Keywords | 2r,6r-hnk Negative emotions Pi3k/akt signaling pathway PTSD Therapy Trauma therapy Ketamine compounds Neuroscience brain path |
| Citations | 3 |
| Key points | (2R,6R)-HNK reversed negative emotional behaviors in stressed rats and modulated PI3K/AKT signaling in the hippocampus and prefrontal cortex. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine for PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells. Mice | 2024 | Experimental animal study | |
| Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD. Rats | 2024 | Animal study | |
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3β/GR signaling of rats. Single prolonged stress-induced PTSD rat model | 2024 | Animal study | |
| (2R, 6R)-hydroxynorketamine ameliorates PTSD-like behaviors during the reconsolidation phase of fear memory in rats by modulating the VGF/BDNF/GluA1 signaling pathway in the hippocampus. Rats (single prolonged stress and contextual fear conditioning models) | 2025 | Animal study |