title: Prophylactic Ketamine Attenuates Learned Fear.
abstract: Ketamine has been reported to be an efficacious antidepressant for major depressive disorder and posttraumatic stress disorder. Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown whether ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience, in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg/kg) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, 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. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic manner 1 week before a stressor, in order to protect against heightened fear responses to aversive stimuli.
authors.affiliation: Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.|Barnard College of Columbia University, New York, NY, USA.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: McGowan
authors.affiliation: Barnard College of Columbia University, New York, NY, USA.|Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, USA.
authors.forename: Christina T
authors.initials: CT
authors.lastname: LaGamma
authors.affiliation: Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Tsitsiklis
authors.affiliation: Department of Psychiatry, Columbia University, NYSPI Kolb Research Annex, New York, NY, USA.|Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Neria
authors.affiliation: Department of Psychiatry, Columbia University, NYSPI Kolb Research Annex, New York, NY, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Brachman
authors.affiliation: Division of Integrative Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, USA.|Department of Psychiatry, Columbia University, NYSPI Kolb Research Annex, New York, NY, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Denny
mesh_terms: D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects*; D004334:Drug Administration Schedule; D005239:Fear / Q000187:drug effects*; D046353:Immobility Response, Tonic / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice
chemical_list: D007649:Ketamine