Effects of Ketamine on Fear Memory Extinction: A Review of Preclinical Literature

Martin Boese ¹ Rina Berman ¹ Kennett Radford ² Luke R Johnson ³ Kwang Choi ^1*

• ¹ Uniformed Services University of the Health Sciences, Bethesda, United States
• ² Walter Reed National Military Medical Center, Bethesda, Maryland, United States
• ³ University of Tasmania, Hobart, Tasmania, Australia

Ketamine, a multimodal dissociative anesthetic drug, is widely used as a trauma analgesic in emergency situations. Ketamine is also used to treat psychiatric disorders due to its broad application potential, including treatment-resistant major depression. However, its impacts on the development of post-traumatic stress disorder (PTSD) and its potential as a treatment for PTSD are controversial. PTSD is a psychiatric disorder marked by persistent and intrusive memories of traumatic event(s) and re-experiencing of the traumatic memories when exposed to trauma-related stimuli. Individuals with PTSD are often treated with cognitive behavioral therapy (CBT) such as prolonged exposure therapy (PE), in which they are reminded of the previous traumatic memory. If successful, individuals with PTSD may learn that the previous traumatic stimuli are no longer threatening, a process known as fear extinction. Although fear extinction can be studied in laboratory animals, previous preclinical literature on the effects of ketamine on fear extinction has been inconsistent. Thus, we summarized the effects of ketamine on fear extinction and its potential molecular mechanisms based on the preclinical studies. Potential reasons for discrepancies in the literature include several factors such as different dosages, routes, and timing of ketamine administration in fear extinction studies. We conclude the review with recommendations for future research on ketamine and PTSD such as the inclusion of more female subjects, clinically relevant doses and routes of ketamine administration, and more comprehensive behavioral assays that are relevant to PTSD in humans to enhance translation between preclinical and clinical research.