Synaptic fusions in regulating sleep and wake activity in mice

Ketamine, an N-methyl-D-aspartate (NMDA) glutamate antagonist, has been reported to be an efficacious antidepressant for depression and posttraumatic stress disorder, and most recently, to be a prophylactic against stress-induced depressive-like behavior. It remains unknown, however, when ketamine should be administered relative to a stressor or depressive episode in order to maximize its beneficial effects. Furthermore, it is unknown if ketamine can be prophylactic against subsequent episodes. Here, we systematically tested the utility of ketamine relative to a fear experience in order to determine the best interval for ketamine to be administered in order to reduce fear or act as a prophylactic against subsequent aversive episodes. Using a 3-shock contextual fear conditioning (CFC) paradigm, we tested if ketamine could alter how 129SvEv mice respond to fear. Mice were administered a single dose of saline or ketamine (30 mg kg) at varying time points before or after CFC, extinction, or reinstatement. Mice administered prophylactic ketamine 1 week before, but not 1 month before, CFC training exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. Interestingly, mice administered ketamine 1 h before CFC exhibited increased freezing behavior when compared with mice administered saline. These data indicate that ketamine can diminish the fear response when given as a prophylactic, but not when given immediately before or after an aversive episode. Therefore, ketamine may be most useful if administered in a vaccine-like fashion to protect against fear-inducing stimuli. Affiliations Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, Barnard College of Columbia University, New York, NY, Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) / New York State Psychiatric Institute (NYSPI), New York, NY, Department of Psychiatry, Columbia University, New York, NY, Department of Epidemiology, Columbia University, New York, NY Funding Support J.C.M. was supported by the Barnard Noyce Teacher Scholars Program, a Columbia University Summer Undergraduate Research Fellowship (SURF), and the Columbia University Summer Program for Under-Represented Students (SPURS). C.T.L. was supported by Barnard College’s Summer Research Institute (SRI). S.C.L. was supported by a NIH DP5 OD017908-01. C.A.D. was supported by a NIH DP5 OD017908-01, a NYSTEM C-021957, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, P&S Investigator.