Ketamine administration reduced conditioned defensive behaviour and upregulated protein expression associated with...

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.