Ketamine alleviates fear memory and spatial cognition deficits in a PTSD rat model via the BDNF signaling pathway of the hippocampus and amygdala
Yue Teng, JiaYao Niu, Yang Liu, Han Wang, Jinhong Chen, Yujia Kong, Xuan Wang, Bo Lian, Hongwei Sun, WeiWeng Wang, Kuitao Yue
Research Square July 3, 2023 preprint DOI: 10.21203/rs.3.rs-3116158/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study |
|---|---|
| Population | Rats subjected to single prolonged stress and electric shock (SPS&S) as a PTSD model |
| Intervention | Ketamine |
| Dose | 5, 10, 15, and 20 mg/kg, i.p. |
| Topics | Esketamine Ketamine PTSD |
| Key points | Ketamine reversed SPS&S-induced fear and spatial memory impairment and restored down-regulated BDNF and PSD-95 signaling in the hippocampus and amygdala, with a U-shaped dose effect: 10–15 mg/kg improved cognition while 15–20 mg/kg reversed benefits. The authors propose that enhanced BDNF–PSD-95 coupling may underlie ketamine's therapeutic effect in PTSD. |
Abstract
Abstract Background Post-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits. Studies have demonstrated that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nonetheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear.
Methods: In this study, different concentrations of ketamine (5, 10, 15, and 20 mg/kg, i.p.) were evaluated in rat models of single prolonged stress and electropodic shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis, immunohistochemistry.
Results: The data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment. The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10–15mg/kg resulted in significant changes in behavioral outcomes. These manifestations of improvements in cognitive function and molecular changes were reversed at high doses (15–20mg/kg).
Conclusion: Overall, ketamine reversed SPS&S-induced fear and spatial memory impairment and the down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. A dose equal to 15 mg/kg rapidly reversed the behavioral and molecular changes, and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 effects could be involved in the therapeutic efficiency of ketamine for PTSD.
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 |