Effects of ketamine, dexmedetomidine and propofol anesthesia on emotional memory consolidation in rats: Consequences for the development of post-traumatic stress disorder

This animal study (n=160) investigated the effects of ketamine (125 mg/kg) on the formation of traumatic memories in rats and found that it increased the retention of fearful memories when administered in close proximity to stress exposure.

Abstract

“Intensive Care Unit (ICU) or emergency care patients, exposed to traumatic events, are at increased risk for Post-Traumatic Stress Disorder (PTSD) development. Commonly used sedative/anesthetic agents can interfere with the mechanisms of memory formation, exacerbating or attenuating the memory for the traumatic event, and subsequently promote or reduce the risk of PTSD development. Here, we evaluated the effects of ketamine, dexmedetomidine and propofol on fear memory consolidation and subsequent cognitive and emotional alterations related to traumatic stress exposure.

Immediately following an inhibitory avoidance training, rats were intraperitoneally injected with ketamine (100–125 mg/kg), dexmedetomidine (0.3-0.4 mg/kg) or their vehicle and tested for 48 h memory retention. Furthermore, the effects of ketamine (125 mg/kg), dexmedetomidine (0.4 mg/kg), propofol (300 mg/kg) or their vehicle on long-term memory and social interaction were evaluated two weeks after drug injection in a rat PTSD model. Ketamine anesthesia increased memory retention without altering the traumatic memory strength in the PTSD model. However, ketamine induced a long-term reduction of social behavior. Conversely, dexmedetomidine markedly impaired memory retention, without affecting long-lasting cognitive or emotional behaviors in the PTSD model. We have previously shown that propofol anesthesia enhanced 48 h memory retention. Here, we found that propofol induced an enduring traumatic memory enhancement and anxiogenic effects in the PTSD model. These findings provide new evidence for clinical studies showing that the use of ketamine or propofol anesthesia in emergency care and ICU might be more likely to promote the development of PTSD, while dexmedetomidine might have prophylactic effects.”

Authors: Maria Morena, Andrea Berardi, Andrea Peloso, Daniela Valeri, Maura Palmery, Viviana Trezza, Gustav Schelling & Patrizia Campolongo

Summary

After trauma, ketamine, dexmedetomidine and propofol injections affect emotional memory consolidation in rats and cause long-lasting cognitive and social alterations.

Intensive Care Unit (ICU) and emergency care patients exposed to traumatic events are at increased risk for Post-Traumatic Stress Disorder (PTSD) development. Ketamine, dexmedetomidine and propofol anesthesia can interfere with the mechanisms of memory formation, exacerbating or attenuating the memory for the traumatic event, and subsequently promote or reduce the risk of PTSD development.

Traumatic and life-threatening events may result in stress-related psychiatric disorders such as Post-Traumatic Stress Disorder (PTSD), which can interfere with daily life and social activities. Anesthetic and sedative agents, such as propofol, ketamine and the 2-adrenoceptor agonist dexmedetomidine, may interfere with memory formation. Ketamine treatment appears to reduce behavioral alterations induced by traumatic stress in two different models of PTSD.

Ketamine was shown to have detrimental effects on animals’ conditioned freezing response, while dexmedetomidine was shown to impair memory formation in rodents. In humans, ketamine use during emergency care correlates with sustained PTSD symptomatology. Anesthetic and sedative agents administered during emergency care or ICU treatment shortly after experiencing a traumatic event may interfere with memory formation and facilitate the occurrence of PTSD later in life. Therefore, it is crucial to understand the effects of commonly used anesthetic/sedative agents on aversive memory formation.

Male Sprague-Dawley rats were kept in an air-conditioned controlled room with food and water available ad libitum. Ketamine, dexmedetomidine, and propofol were dissolved in saline solution (0.9%) and administered by intraperitoneal injection immediately after the inhibitory avoidance training trial or immediately after the exposure session of the PTSD model.

Rats were trained and tested in an inhibitory avoidance apparatus, which consists of a trough-shaped alley divided into two compartments.

Rats were placed into a shock compartment, which was not illuminated, and were shocked for 1 s. Retention was tested 48h later, and longer latencies indicating better memory retention were interpreted as better. Rats were habituated to a metal trough-shaped box for 5 min, then exposed to 5 footshocks (2 s, 0.8 mA) randomly placed in the box for 2 min, followed by a 60 s rest period. Memory retention was evaluated over a 10-min period by analyzing contextual freezing behavior.

To evaluate the level of emotional distress, 48h after the re-exposure session, rats were tested in a social interaction test. They were put in a quadrangular arena for 10 min under red lights conditions. In this test, rearing and wall rearing were considered non-social behaviors, and following, sniffing, pouncing, pinning, boxing, and crawling over were considered social behaviors. The social interaction time was obtained by summing together all the discrete durations of each social behavior. To reduce bias, rats were randomly assigned to each experimental condition. The sleeping duration of ketamine and dexmedetomidine was measured in different groups of rats, and the time between loss and recovery of righting reflex for each rat was defined as sleeping time.

The study used paired t-tests to determine whether learning had occurred in the inhibitory avoidance training. ANOVA was used to analyze the data.

After footshock, ketamine administration did not affect inhibitory avoidance memory. However, vehicle-treated rats retained memory of the shock experience.

Ketamine treatment significantly prolonged retention latencies compared to vehicle-treated rats. After training, rats were given immediate posttraining administration of anesthetic doses of dexmedetomidine and tested for memory retention 48h later. Rats treated with dexmedetomidine had significantly shorter retention latencies than those of vehicle-treated rats. Based on the above described results and our previous study [17], we next examined the effects of post-trauma anesthetic administration on cognitive and emotional symptoms of PTSD in rats. Ketamine- and propofol-treated rats spent significantly less time interacting with the social partner than vehicle-treated rats.

The present findings show that ketamine and dexmedetomidine have a profound impact on fear memory consolidation, but only ketamine enhances memory retention, whereas dexmedetomidine decreases memory retention. Interestingly, both drugs induce persistent and pronounced emotional dysfunctions in rats exposed to traumatic stress. Previous studies in animals have demonstrated that acute or chronic sub-anesthetic doses of ketamine impair memory processes, but the effects of ketamine on fear memory consolidation are controversial.

Ketamine use in emergency care correlates with sustained PTSD symptoms, while dexmedetomidine use reduces fear memory consolidation without altering symptoms associated with PTSD. These results suggest that dexmedetomidine use after experiencing a traumatic event might prevent PTSD development. Dexmedetomidine is a potent agonist of the 2b-adrenergic receptor subtype, and individuals carrying the Glu(301)-Glu(303) deletion variant of the gene coding for this receptor subtype exhibit enhanced emotional memory. Propofol, however, strongly potentiates memory consolidation for aversive experience, exacerbating, at the same time, symptoms of social anxiety. Our results strongly suggest that the choice of anesthetic/sedative agent in ICU patients is critical, as the drug used might differentially affect cognitive processes of traumatic memory consolidation, either triggering or preventing the occurrence of PTSD. Propofol, ketamine and dexmedetomidine should be used with caution in patients undergoing emergency care or ICU treatment, as they may promote the formation of traumatic memory and induce long-term alterations in cognitive and emotional processes.

Source of Funding

Figure 1 shows that immediate posttraining injection of ketamine enhanced memory retention, whereas immediate posttraining injection of dexmedetomidine impaired memory retention.

Post-trauma exposure injection of ketamine, dexmedetomidine or propofol did not affect freezing behavior or social interaction time, but increased the percentage of freezing time and decreased the social interaction time, respectively.

Ketamine, dexmedetomidine and propofol affected the durations of social and non-social behavior parameters during the social interaction test.