Effects of Ketamine on Rodent Fear Memory

Abstract

Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder (PTSD) remains controversial. To address these concerns, preclinical studies have investigated the effects of ketamine administration on fear memory and stress-related behaviors in laboratory animals. Despite a well-documented line of research examining the effects of ketamine on fear memory, there is a lack of literature reviews on this important topic. Therefore, this review article summarizes the current preclinical literature on ketamine and fear memory with a particular emphasis on the route, dose, and timing of ketamine administration in rodent fear conditioning studies. Additionally, this review describes the molecular mechanisms by which ketamine may impact fear memory and stress-related behaviors. Overall, findings from previous studies are inconsistent in that fear memory may be increased, decreased, or unaltered following ketamine administration in rodents. These conflicting results can be explained by factors such as the route, dose, and timing of ketamine administration; the interaction between ketamine and stress; and individual variability in the rodent response to ketamine. This review also recommends that future preclinical studies utilize a clinically relevant route of administration and account for biological sex differences to improve translation between preclinical and clinical investigations.

Keywords: PTSD; fear conditioning; fear memory; intravenous; ketamine; stress.

Figure 1

Summary of ketamine’s proposed molecular mechanisms. CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotropic hormone; HPA, hypothalamic–pituitary–adrenal; GABA, gamma-aminobutyric acid; AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDA, N-methyl-D-aspartate receptor; TrkB, tropomyosin receptor kinase B; BDNF, brain-derived neurotrophic factor; AKT, protein kinase B; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; Egr1, early growth response 1; Ca²⁺, calcium. This illustration was created using Biorender.com.