Ketamine administration reduced conditioned defensive behaviour and upregulated protein expression associated with neuroplasticity in a planarian model of aversive memory reactivation.
Fionnghuala L J James, Sayed K Ahamed, Cheng-I Yang, Richard Wilson, Juan J. Canales, Carmelo M Vicario, Luke R Johnson, Vanni Caruso
Progress in neuro-psychopharmacology & biological psychiatry October 17, 2026 DOI: 10.1016/j.pnpbp.2026.111979 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Sample size | 15 |
| Population | Brown planaria (Girardia dorotocephala) |
| Intervention | Ketamine |
| Dose | 10 μM, 1 μM |
| Topics | Ketamine Neuroplasticity PTSD Esketamine |
| Keywords | Planaria Proteomics Threat memory |
| Key findings | In brown planaria undergoing aversive memory reactivation, 10 μM ketamine significantly reduced defensive behaviors (scrunching, C-shape movements, head turns) compared with vehicle controls. Proteomic analysis showed enrichment of pathways associated with rapid neuronal growth, synaptic plasticity, and cellular mRNA changes. The authors propose that ketamine may disrupt conditioned aversive memory via rapid neuronal restructuring and augmented synaptic plasticity. |
Abstract
Traumatic memories that are resistant to modification or extinction are a characteristic feature of post-traumatic stress disorder (PTSD). The process of fear memory reconsolidation has been identified as a potential therapeutic target for the treatment of PTSD. Ketamine, an NMDA receptor antagonist with dissociative properties, has been identified as a drug with high therapeutic potential for this target, as it destabilises traumatic memory while enabling rapid modification and update of the memory to no longer be threatening. However, its exact mechanisms of action on reducing the impact of aversive memory remains poorly understood. To better understand these mechanisms, a conditioned aversive memory reactivation model using ketamine was carried out in brown planaria (Girardia dorotocephala), an invertebrate model that shows a high degree of conservation in neural anatomy, receptors, neurotransmitters, and learning behaviours, while being comparatively simpler than standard mammalian models. In this study, 15 planaria were randomly assigned to three treatment groups (10 μM ketamine, 1 μM ketamine, vehicle control) and underwent a classical aversive memory reactivation paradigm. Whole planaria were processed for an exploratory proteomic analysis to analyse changes in protein expression associated with the effects of ketamine on the aversive memory reactivation process. Behavioural data showed a significant reduction in defensive behaviours, including scrunching movements F(2,12) = 11.85, p = 0.0014, ƞ2 = 0.66, C-shape movements F(2,12) = 6.59, p = 0.012, ƞ2 = 0.52, and head turns F(2,12) = 9.59, p = 0.0032, ƞ2 = 0.61, in the 10 μM ketamine group on the final test day compared to vehicle controls. Proteomic analysis showed that these behavioural changes were accompanied by a high degree of enrichment in molecular pathways associated with rapid neuronal growth and synaptic plasticity, and changes in cellular mRNA, all markers of learning. These preliminary findings in an invertebrate model improve understanding of how ketamine may facilitate disruption of conditioned aversive memory via rapid neuronal restructuring and augmenting synaptic plasticity.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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In planaria undergoing aversive memory reactivation, 10 μM ketamine reduced defensive behaviors and was associated with protein pathways linked to synaptic plasticity.
Synthesized
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 |
Citations in the library
Cites 13
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- Ketamine: Neuroprotective or Neurotoxic? Frontiers in Neuroscience September 10, 2021
- Long term structural and functional neural changes following a single infusion of Ketamine in PTSD Neuropsychopharmacology June 3, 2023
and 8 more in the library