(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.
Han Wang, Yuxuan He, Jiahao Tang, Yang Liu, Chunyan Wu, Changjiang Li, Hongwei Sun, Lin Sun
Behavioural Brain Research January 5, 2025 DOI: 10.1016/j.bbr.2024.115273 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Rats (single prolonged stress and contextual fear conditioning models) |
| Interventions | (2R 6R)-hydroxynorketamine |
| Dose | 0.5 nmol in 5 μL |
| Topics | PTSD |
| Keywords | 2r 6r-hydroxynorketamine Acquisition Extinc-tion Vgf PTSD Therapy Memory reconsolidation Ketamine research Neuroscience breakthroughs Trauma treatment |
| Citations | 5 |
| Key points | (2R,6R)-HNK administration during the reconsolidation phase, but not acquisition or extinction phases, alleviates PTSD-like behaviors and restores hippocampal GluA1, VGF, and BDNF protein levels in rats. |
Abstract
Fear memory, a fundamental symptom of post-traumatic stress disorder (PTSD), is improved by (2R, 6R)-hydroxynorketamine ((2R, 6R)-HNK) administration. However, the phase of fear memory in which the injected drug is the most effective at mitigating PTSD-like effects remains unknown. This study aimed to explore the effects of (2 R, 6 R)-HNK administration during three phases [acquisition (AP), reconsolidation (RP), and extinction (EP)] on PTSD-like behaviors in single prolonged stress (SPS) and contextual fear conditioning (CFC) rat models. The effects of VGF-inducible type of nerve growth factor (VGF), brain-derived neurotrophic factor (BDNF), and GluA1 on hippocampus (HIP) expression were also explored. SPS and CFC (SPSC) were used to establish a PTSD rat model. After lateral ventricle injection of 5 μL (2 R, 6 R)-HNK (0.5 nmol). Anxiety-depression-like behaviors were assessed in rats by the open field test (OFT) and elevated plus maze test (EPMT). Situational fear responses were evaluated in rodents by freezing behavior test (FBT) test. In addition, GluA1, VGF, and BDNF were assessed in the hippocampus by Western blot assay (WB) and Immunohistochemistry assay (IF). SPSC procedure induced PTSD-like behaviors. The SPSC group had decreased spontaneous exploratory behavior and increased fear response. The (2R, 6R)-HNK group showed improved SPSC-induced reduction in GluA1, VGF, and BDNF levels in the HIP. During RP, anxiety and fear avoidance behaviors were alleviated, and the protein levels of GluA1, VGF, and BDNF in the HIP were restored. In contrast, no significant improvement was noted during AP and EP. (2R,6R)-HNK modulates the VGF/BDNF/GluA1 signaling pathway in the hippocampus and improves PTSD-like behaviors during the reconsolidation phase of fear memory in rats, which may provide a new target for the clinical treatment and prevention of fear-related disorders such as PTSD.