Time‐Dependent Therapeutic Effect of <i>S</i> ‐Ketamine on PTSD Mediated by VTA‐OFC Dopaminergic Neurocircuit
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 VTA<sup>DA</sup> neurons consecutively decrease following PTSD modeling and are restored by early S-Ketamine intervention. In particular, VTA<sup>DA</sup> neurons respond to the conditioned stimuli, mediating the replacement of aversive memory encoding during fear extinction. The inhibition of VTA<sup>DA</sup>-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 VTA<sup>DA</sup>-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.
Authors
- Jiannan Li (ORCID: https://orcid.org/0000-0001-9744-7666)
- Hailong Dong (ORCID: https://orcid.org/0000-0001-8984-9067)
- Zhongmin Fan (ORCID: https://orcid.org/0000-0002-3816-4284)
- Sa Wang (ORCID: https://orcid.org/0000-0001-6372-7352)
- Yunyun Zhang (ORCID: https://orcid.org/0000-0001-7744-0141)
- Jinghao Wang (ORCID: https://orcid.org/0000-0001-8696-6911)
- Jing Mao (ORCID: https://orcid.org/0000-0002-1122-5438)
- Rui Wang (ORCID: https://orcid.org/0000-0002-5714-0202)
- Pengfei Wei
- Yumei Wu (ORCID: https://orcid.org/0000-0002-8524-1254)
- Quanying Liu (ORCID: https://orcid.org/0000-0002-2501-7656)
- Guangchao Zhao (ORCID: https://orcid.org/0000-0001-7842-3773)
- Lei Liu (ORCID: https://orcid.org/0000-0001-5418-1845)
- Min Wang (ORCID: https://orcid.org/0000-0002-7736-4625)
- Xinxin Zhang (ORCID: https://orcid.org/0000-0002-2918-9447)
- Ye Wang (ORCID: https://orcid.org/0000-0001-6073-4688)
- Hui Wang (ORCID: https://orcid.org/0000-0002-2346-8621)
- Huiming Li (ORCID: https://orcid.org/0000-0001-5536-7166)
- Min Cai (ORCID: https://orcid.org/0000-0003-0027-0150)
- Dan Wang (ORCID: https://orcid.org/0000-0002-2586-066X)
- Rou Xue (ORCID: https://orcid.org/0009-0001-4627-6980)
Institutions
- Shanxi Medical University (CN)
- Southern University of Science and Technology (CN)
- Shaanxi Provincial People's Hospital (CN)
- Xijing Hospital (CN)
- Shanxi Provincial People’s Hospital (CN)
- Southeast University (CN)
- Air Force Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1002/advs.202500805
- Citations
- 2
- Primary Topic
- Treatment of Major Depression
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- National Natural Science Foundation of China
- Fourth Military Medical University
- National Science and Technology Major Project