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. 2025 Apr 30:19:1546460.
doi: 10.3389/fnins.2025.1546460. eCollection 2025.

Effects of ketamine on fear memory extinction: a review of preclinical literature

Martin Boese  1 , Rina Berman  2 , Kennett Radford  3 , Luke R Johnson  2   4   5 , Kwang Choi  1   2   5
Affiliations

Effects of ketamine on fear memory extinction: a review of preclinical literature

Martin Boese et al. Front Neurosci. .

Abstract

Introduction: Ketamine, a multimodal dissociative anesthetic, is widely used as a trauma analgesic in emergency situations. Ketamine is also used to treat psychiatric disorders due to its broad application potential, including treatment-resistant major depression. However, its impacts on the development of post-traumatic stress disorder (PTSD) and its potential as a treatment for PTSD are controversial. PTSD is marked by persistent and intrusive memories of traumatic event(s) and re-experiencing of the traumatic memories when exposed to trauma-related stimuli. Individuals with PTSD are often treated with prolonged exposure therapy (PE), in which they are gradually exposed to stimuli that remind them of the previous traumatic memory. If successful, they may learn that the previously traumatic stimuli are no longer threatening, a process known as fear extinction. Although fear extinction can be studied in laboratory animals, previous preclinical literature on the effects of ketamine on fear extinction has been inconsistent.

Methods: Thus, we summarized the existing preclinical literature examining effects of ketamine on fear extinction and its potential molecular mechanisms.

Results: Studies found that ketamine may enhance, impair, have no effect, or have mixed effects on fear extinction. These discrepancies may be attributed to differences in dosage, route, and timing of ketamine administration.

Discussion: We conclude the review with recommendations for future research on ketamine and PTSD such as the inclusion of more female subjects, clinically relevant doses and routes of ketamine administration, and more comprehensive behavioral assays that are relevant to PTSD in humans to enhance translation between preclinical and clinical research.

Keywords: cognitive behavioral therapy (CBT); fear extinction; fear memory; ketamine; molecular mechanism; posttraumatic stress disorder (PTSD); review; translational research.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanisms of ketamine on fear memory extinction. GABA, gamma-aminobutyric acid; NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; TrkB, tyrosine receptor kinase B; BDNF, brain-derived neurotrophic factor; mTOR, mammalian/mechanistic target of rapamycin; Ca++, calcium; eEF2, eukaryotic translation elongation factor 2.
Figure 2
Figure 2
Auditory fear conditioning in rodents. (A) Prior to fear conditioning, an animal does not respond to a neutral conditioned stimulus (CS). (B) CS is paired with a noxious unconditioned stimulus, such as foot shock. (C) Following fear conditioning, the animal recalls fearful memory and displays fear behavior when presented with CS. (D, E) Fear memory extinction: after repeated, unreinforced exposures to the CS, the animal learns that the CS no longer represents a threat, and fear memory behaviors are reduced or eliminated.
Figure 3
Figure 3
PRISMA flow diagram for literature search and review.
See this image and copyright information in PMC

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References

    1. Abdallah C. G., Roache J. D., Gueorguieva R., Averill L. A., Young-McCaughan S., Shiroma P. R., et al. . (2022). Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology 47, 1574–1581. 10.1038/s41386-022-01266-9 - DOI - PMC - PubMed
    1. Albott C. S., Lim K. O., Forbes M. K., Erbes C., Tye S. J., Grabowski J. G., et al. . (2018). Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J. Clin. Psychiatry 79:17m11634. 10.4088/JCP.17m11634 - DOI - PubMed
    1. Aleksandrova L. R., Phillips A. G. (2021). Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol. Sci. 42, 929–942. 10.1016/j.tips.2021.08.003 - DOI - PubMed
    1. Aleksandrova L. R., Phillips A. G., Wang Y. T. (2017). Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J. Psychiatry Neurosci. 42, 222–229. 10.1503/jpn.160175 - DOI - PMC - PubMed
    1. Almeida T. M., Lacerda da Silva U. R., Pires J. P., Borges I. N., Martins C. R. M., Cordeiro Q., et al. . (2024). Effectiveness of ketamine for the treatment of post-traumatic stress disorder - a systematic review and meta-analysis. Clin. Neuropsychiatry 21, 22−31. 10.36131/cnfioritieditore20240102 - DOI - PMC - PubMed

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