Memories reactivated under ketamine are subsequently stronger: A potential pre-clinical behavioral model of psychosis

Background: Sub-anesthetic doses of the NMDA antagonist ketamine have been shown to model the formation and stability of delusion in human subjects. The latter has been predicted to be due to aberrant prediction error resulting in enhanced destabilization of beliefs. To extend the scope of this model, we investigated the effect of administration of low dose systemic ketamine on memory in a rodent model of memory reconsolidation. Methods: Systemic ketamine was administered either prior to or immediately following auditory fear memory reactivation in rats. Memory strength was assessed by measuring freezing behavior 24 h later. Follow up experiments were designed to investigate an effect of pre-reactivation ketamine on short-term memory (STM), closely related memories, and basolateral amygdala (BLA) specific destabilization mechanisms. Results: Rats given pre-reactivation, but not post-reactivation, ketamine showed larger freezing responses 24 h later compared to vehicle. This enhancement was not observed 3 h after the memory reactivation, nor was it seen in a closely related contextual memory. Prior inhibition of a known destabilization mechanism in the BLA blocked the effect of pre-reactivation ketamine. Conclusions: Pre- but not post-reactivation ketamine enhances fear memory. These data together with recent data in human subjects supports a model of delusion fixity that proposes that aberrant prediction errors result in enhanced destabilization and strengthening of delusional belief. (C) 2015 Elsevier B.V. All rights reserved.