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

Traumatic or life‑threatening experiences can lead to stress‑related disorders such as Post‑Traumatic Stress Disorder (PTSD), which is marked by persistent recollection of the event, high emotional distress on cue exposure, avoidance and social impairment. Patients treated in emergency care or in intensive care units (ICU) are at particular risk because anaesthetic and sedative drugs administered around the time of trauma may interact with neurotransmitter systems involved in emotional memory formation and thereby influence consolidation of traumatic memories. Previous preclinical and clinical studies have reported inconsistent results for commonly used agents such as ketamine, propofol and the α2‑adrenoceptor agonist dexmedetomidine: some reports indicate memory impairment, others enhancement, and clinical correlations with PTSD symptoms have been observed in some settings but not others. Morena and colleagues set out to determine whether anaesthetic doses of ketamine or dexmedetomidine, administered immediately after an aversive event, alter consolidation of fear memory in rats, and to compare ketamine, dexmedetomidine and propofol in a rat model of PTSD. The study examined short‑term retention in an inhibitory avoidance task (single footshock, retention tested at 48 h) and longer‑term traumatic memory and emotional behaviour after a multi‑shock PTSD‑like exposure (five footshocks, re‑exposure at 14 days, social interaction assessed thereafter). The investigators aimed to clarify whether post‑trauma administration of these agents might increase or reduce the risk of PTSD‑like outcomes.

The study used adult rats and two behavioural paradigms. Inhibitory avoidance training involved a single inescapable footshock (0.35 mA, 1 s); animals received the drug immediately after training and retention was tested 48 h later by measuring step‑through latency (600 s cutoff). The PTSD model used a trough‑shaped box in which, after habituation, rats received five randomized footshocks (2 s, 0.8 mA) over a 5‑minute exposure session; animals were re‑exposed to the context 14 days later and contextual freezing (percentage time freezing during 10 min) was the primary memory measure. Emotional consequences were assessed 48 h after re‑exposure using a 10‑minute social interaction test in unfamiliar same‑treatment pairs, with social behaviours summed to yield social interaction time. Drugs and dosing were chosen to produce anaesthesia of at least ~30 min on average after a single intraperitoneal injection. Ketamine was given at 100 or 125 mg/kg, dexmedetomidine at 0.3 or 0.4 mg/kg (some sleeping‑time measures referenced 0.2–0.3 mg/kg), and propofol at 300 mg/kg (dissolved in sesame oil). For the PTSD model, doses selected were those that affected inhibitory‑avoidance retention (125 mg/kg ketamine, 0.4 mg/kg dexmedetomidine, 300 mg/kg propofol). Sleeping duration was measured by loss and recovery of the righting reflex with predefined operational criteria; propofol sleeping time had been previously evaluated by the laboratory. Experimental design features intended to reduce bias included a pre‑experiment sample size calculation (power 0.80, assumed effect size 40%–50%), random assignment to conditions and blinded outcome assessment. The extracted text does not clearly report exact group sizes for each comparison (it states that the number of rats per group is indicated in figure legends). Statistical analyses used paired t‑tests to confirm learning in vehicle groups for inhibitory avoidance, and one‑way ANOVA with treatment as a between‑subjects factor for other measures, followed by Tukey‑Kramer post‑hoc tests; data are presented as mean ± SEM and P < 0.05 was considered significant.

Inhibitory avoidance: Baseline step‑through latencies during training were similar across groups (mean 11.19 ± 1.41 s for the ketamine experiment; 10.96 ± 1.81 s for the dexmedetomidine experiment), indicating no pre‑training differences. Vehicle‑treated rats showed significant retention at 48 h versus training in both experiments. For ketamine, one‑way ANOVA on retention latencies showed a significant treatment effect (F2,36 = 3.56, P = 0.04). Post‑hoc testing indicated that ketamine at 125 mg/kg produced significantly longer retention latencies than vehicle (P < 0.05), consistent with enhanced memory retention; the lower ketamine dose (100 mg/kg) did not alter retention. Dexmedetomidine produced the opposite effect in the inhibitory avoidance task. One‑way ANOVA for 48 h retention latencies showed a significant effect of treatment (F2,33 = 8.09, P = 0.001), and post‑hoc comparisons revealed that both 0.3 and 0.4 mg/kg doses led to significantly shorter retention latencies than vehicle (P < 0.01), indicating impaired memory consolidation. PTSD model and emotional outcomes: For the PTSD paradigm the investigators compared ketamine (125 mg/kg), dexmedetomidine (0.4 mg/kg) and propofol (300 mg/kg) administered immediately after the multi‑shock exposure. The authors combined multiple vehicle groups into a single pooled vehicle sample (14 rats randomly chosen from vehicle groups). One‑way ANOVA on contextual freezing at re‑exposure (14 days) found a significant treatment effect (F3,50 = 4.76, P = 0.005); post‑hoc tests showed that propofol‑treated rats froze more than both vehicle and dexmedetomidine groups (P < 0.05), indicating a stronger long‑term traumatic memory after propofol. In the social interaction test, one‑way ANOVA also indicated a treatment effect (F3,50 = 4.04, P = 0.01). Post‑hoc comparisons showed that animals treated with ketamine or propofol spent significantly less time interacting than vehicle‑treated rats (P < 0.05), consistent with increased social anxiety or emotional distress. Dexmedetomidine did not reduce social interaction relative to vehicle. The extracted text refers to further breakdowns of social and non‑social behaviours in a table, but those detailed values are not included here.

Morena and colleagues interpret their findings as showing that anaesthetic doses of ketamine and dexmedetomidine differentially affect fear memory consolidation: ketamine enhanced retention in the inhibitory avoidance task, whereas dexmedetomidine impaired it. The investigators note these effects were transient and task‑specific, since neither ketamine nor dexmedetomidine altered traumatic long‑term contextual memory in the PTSD model, whereas propofol produced a marked potentiation of traumatic memory measured two weeks later. Behaviourally, both ketamine and propofol induced long‑lasting emotional dysfunction in trauma‑exposed animals, as evidenced by reduced social interaction, whereas dexmedetomidine did not produce such emotional sequelae. The authors place these results in the context of prior animal and clinical work. They acknowledge heterogeneous findings in the literature for ketamine—where sub‑anesthetic and chronic regimens have produced memory impairments in some paradigms but fear‑enhancing effects in others—and cite human associations between emergency ketamine use and sustained PTSD symptoms as consistent with their observation of post‑trauma emotional distress after ketamine. By contrast, dexmedetomidine's memory‑impairing profile and its reduction of fear consolidation align with prior rodent studies that also linked dexmedetomidine to decreased neuronal activation markers (c‑Fos, P‑CREB) in the amygdala. The authors suggest this pharmacological profile may explain clinical observations that dexmedetomidine‑sedated ICU patients have reduced delirium duration. Regarding propofol, the investigators reiterate their prior finding that post‑trauma propofol potentiates aversive memory and note that timing differences (pre‑ versus post‑exposure administration) across studies may account for apparently contradictory reports of propofol‑induced amnesia. The study team emphasises the translational relevance of the post‑trauma administration paradigm, arguing that sedation or anaesthesia provided immediately after trauma—common in emergency or ICU care—occurs when memory consolidation processes are active and thus may influence later PTSD risk. They conclude that choice of sedative/anaesthetic agent could either trigger or prevent development of stress‑related disorders and recommend cautious use of propofol and ketamine in settings where patients have recently experienced trauma, while noting dexmedetomidine may have a safer profile. The extracted text does not provide a formal limitations paragraph; methodological differences with other studies are discussed as context for conflicting findings.

The authors conclude that propofol, and to a lesser extent ketamine, administered after a traumatic event may promote formation of traumatic memory and long‑term cognitive and emotional alterations, potentially increasing the likelihood of stress‑related disorders such as PTSD. Conversely, dexmedetomidine appears to reduce fear memory strength and to prevent subsequent emotional distress in this animal model. Morena and colleagues suggest these findings warrant further clinical studies to optimise sedation and anaesthesia practices in emergency and ICU care with the aim of prophylaxis and reduced PTSD risk.