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.

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

“…Accordingly, it was suggested that ketamine is effective when administered before, but not after, exposure to stressors ( McGowan et al, 2017 ). On the other hand, consistent with our results, a number of studies reported a reduction of fear both when ketamine was administered before ( McGowan et al, 2017 , 2018 ; Chen B. K et al, 2020 ) or after stress ( Duclot et al, 2016 ; Girgenti et al, 2017 ; Asim et al, 2020 ; Radford et al, 2020 ), although some inconsistencies were found ( Choi et al, 2020 ). Overall, this suggests that ketamine can affect previously established fear memory, thus improving the recovery from traumatic experiences.…”

Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress

“…Ketamine at high doses interferes with fear memory and extinction consolidation ( Clifton et al, 2018 ; Duclot et al, 2016 ), while lower doses (10 mg/kg) facilitate memory consolidation ( Radford et al, 2018 ). The effects of ketamine on fear memory depend on route of administration as well as dose ( Choi et al, 2020 ). Ketamine at low doses, given intraperitoneally, accelerates FE learning via mTORC1 signaling, a downstream target of BDNF receptor activation ( Girgenti et al, 2017 ).…”

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

“…This is especially important given that ketamine may be an effective treatment of post-traumatic stress disorder [ 106 ], a condition in which patients fail to recover from a traumatic event due to the persistence of the traumatic memory. While preclinical findings with ketamine have so far been inconsistent with regard to the extinction of learned fear [ 107 ], understanding the effects of ( 2R,6R )-HNK on threat-aggravated memory will be an important step toward understanding its potential effectiveness in stress-related disorders and its unique therapeutic mechanism of action.…”