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 24h 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 24h later compared to vehicle. This enhancement was not observed 3h 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.
Yale University Department of Psychiatry, Division of Molecular Psychiatry, Connecticut Mental Health Center, Abraham Ribicoff Research Facility, 34 Park Street, New Haven 06511, United States.
Michael J
MJ
Honsberger
Yale University Department of Psychiatry, Division of Molecular Psychiatry, Connecticut Mental Health Center, Abraham Ribicoff Research Facility, 34 Park Street, New Haven 06511, United States.
Jane R
JR
Taylor
Yale University Department of Psychiatry, Division of Molecular Psychiatry, Connecticut Mental Health Center, Abraham Ribicoff Research Facility, 34 Park Street, New Haven 06511, United States.
Philip R
PR
Corlett
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005239:Fear / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000517:prevention & control; D011618:Psychotic Disorders / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine
Fear conditioning; Ketamine; Reconsolidation; Schizophrenia