Effects of Ketamine on Fear Sensitization

Abstract

Post-traumatic stress disorder (PTSD) is an anxiety disorder characterized by overactive fear responses. Fear learning and memory is modulated in part by the NMDA receptor. Previous studies found that blocking the NMDA receptor rapidly reverses the symptoms of chronic stress such as those observed in PTSD. However, we are unaware if NMDA antagonists block fear sensitization. The present study tested the hypothesis that the NMDA receptor antagonist ketamine prevents fear sensitization. Long-Evans rats were randomly assigned into four treatment groups: Stress with ketamine, no stress with ketamine, stress with vehicle and no stress with vehicle. Rats were administered a single dose of vehicle (0.0 mg/kg) or a sub-anesthetic dose of ketamine (10.0 mg/kg) via intraperitoneal injection following either 22 minutes of footshock stress or no stress. Twenty-four hr later, rats were exposed to 70 db auditory clicks each day for 5 consecutive days in a habituation box. Results showed that ketamine-dosed rats exhibited significantly higher freezing levels during the 5 habituation days compared to controls. Results provide novel information suggesting that inhibition of the NMDA receptor increases sensitized fear behavior elicited by a loud auditory stimulus. That ketamine-treated rats persisted in exhibiting fear sensitization further suggests that an acute sub-anesthetic dose of ketamine induces a long term effect on brain processes involved in behavioral habituation. Additional studies may eventually lead to a clear understanding of the role of NMDA receptor systems in fear sensitization and the pathogenesis of PTSD.