Time‐Dependent Therapeutic Effect of S ‐Ketamine on PTSD Mediated by VTA‐OFC Dopaminergic Neurocircuit
Ye Wang, Lei Liu, Jinghao Wang, Jiannan Li, Huiming Li, Rui Wang, Hui Wang, Min Wang, Quanying Liu, Zhongmin Fan, Yunyun Zhang, Xinxin Zhang, Dan Wang, Sa Wang, Rou Xue, Jing Mao, Min Cai, Pengfei Wei, Hailong Dong, Yumei Wu, Guangchao Zhao
Advanced Science September 25, 2025 DOI: 10.1002/advs.202500805 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Rodent models of PTSD |
| Interventions | S-Ketamine temporally interfering brain stimulation |
| Topics | Esketamine Ketamine PTSD |
| Keywords | Mechanism biology Therapeutic effect Therapeutic approach Drug Stimulation Dopaminergic pathways Glutamate receptor Schizophrenia object-oriented programming |
| Citations | 2 |
| Key points | Early but not late administration of S-Ketamine ameliorates PTSD symptoms by restoring VTA dopamine neuron activity and replacing aversive memory encoding during fear extinction via the VTA-OFC neurocircuit. |
Abstract
Current pharmacotherapies for post-traumatic stress disorder (PTSD) are limited by delayed onset and side effects. Despite ketamine exhibiting rapid relief of the core symptoms of PTSD, its clinical efficacy varies considerably depending on the timing of drug delivery. However, the underlying mechanism remains unclear. In this study, the therapeutic effects of early (day 1) and late (day 7) administration of S-Ketamine on behavioral phenotypes in rodent's models of PTSD are compared. It is observed that early rather than late administration of S-Ketamine significantly ameliorates PTSD symptoms, especially impaired fear extinction. The firing and burst rates of VTADA neurons consecutively decrease following PTSD modeling and are restored by early S-Ketamine intervention. In particular, VTADA neurons respond to the conditioned stimuli, mediating the replacement of aversive memory encoding during fear extinction. The inhibition of VTADA-OFC interrupts the PTSD treatment induced by S-Ketamine. A non-invasive temporally interfering brain stimulation targeting the OFC is further developed, sensitizing cortical dopaminergic transmission and extending the effective time window of S-Ketamine for anti-PTSD. Overall, a neural mechanism for the heterogeneous VTADA-OFC neurocircuit-mediated time-dependent therapeutic effect of S-Ketamine is illustrated. In addition, a novel technique is developed to optimize the strategy of ketamine-assisted psychotherapy for PTSD treatment.
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 |