This animal study (n=206) investigated the effects of ketamine (125 mg/kg) on fearful memory consolidation associated with traumatic events and found that ketamine enhances the formation of these memories only when administered in close proximity to the trauma, partially via sympathetic stimulation which releases noradrenaline.
Abstract
“Introduction: Trauma patients treated with ketamine during emergency care present aggrCampolongoavated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects.
Methods/Results: We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism.
Discussion: Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.”
Authors: Maria Morena, Paola Colucci, Giulia F. Mancini, Valentina De Castro, Andrea Peloso, Gustav Schelling & Patrizia Campolongo
Summary
Trauma patients treated with ketamine during emergency care present aggravated early post-traumatic stress reaction, which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. Ketamine anesthesia may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories.
- Introduction
Trauma victims present increased risk of developing post-traumatic stress disorder (PTSD), which is characterized by altered memory processing of the traumatic experience. Ketamine is an intravenous anesthetic commonly used in clinics, particularly in emergency care, for premedication, sedation, induction and maintenance of general anesthesia.
Stressful events trigger the release of adrenaline, which activates the noradrenergic system in the nucleus of the solitary tract and LC, resulting in enhanced memory for these events.
Trauma victims and patients in emergency care often experience stressful events shortly before ketamine administration. This phase is characterized by a rapid surge of adrenaline/noradrenaline levels.
Evidence suggests that ketamine increases the risk of PTSD development when given in close proximity to the trauma, but that treatment with the -adrenoceptor antagonist propranolol reduces fear and PTSD development when paired with behavioral therapy soon after trauma and ameliorates the symptomatology when PTSD is already developed. We have shown that dexmedetomidine reduces, while ketamine enhances memory retention and exacerbates PTSD symptomatology, when injected soon after a traumatic event. We then explored the role of the adrenergic system in mediating such effects.
2.1. Animals
Two hundred and six male nave Sprague-Dawley rats were used in the present investigation. They were kept in an air-conditioned controlled room with food and water available ad libitum.
2.2. Drug treatment
Propranolol and ketamine were dissolved in saline solution and administered intraperitoneally or intracranially, respectively, 30 min before and after the inhibitory avoidance training trial. Lidocaine and propranolol were administered centrally in a separate experiment. Post-training central infusions of drugs were made using a 30-gauge injection needle connected to a 10-L Hamilton microsyringe driven by a minipump. The infusion volumes were chosen on the basis of previous experiments.
2.4. Adrenal medullectomy
Adrenal medullectomy (ADMX) was performed on rats with isoflurane, and the adrenal glands were removed. The rats were given saline to drink for 1 week after surgery to compensate for salt and water losses during the period of corticosteroid deficiency.
2.5. Inhibitory avoidance test
Rats were trained and tested in an inhibitory avoidance apparatus, consisting of a trough-shaped alley divided into two compartments, separated by a sliding door. The rats were handled 1 min each for 3 days before training, and the apparatus was cleaned with a 70% ethanol solution after each session.
2.6. Sleep parameters
Sleep onset time and duration were measured for rats given ketamine. The time between loss and recovery of righting reflex was defined as the time between anesthetic injection and the time the rat was able to turn itself upright.
2.7. Histology
To check for cannula placement, rats were anesthetized with sodium pentobarbital and perfused transcardially with 0.9% saline. Their brains were removed and immersed in a 4% formaldehyde solution for 48 h before sectioning.
2.8. Statistical analysis
Rats were tested for inhibitory avoidance learning and sleep duration. Statistical analysis was performed using GraphPad Prism Software and P values of 0.05 were considered statistically significant.
3.1. Immediate post-training, but not delayed, ketamine injection enhances aversive memory retention
We previously showed that ketamine enhances 48-h memory retention in rats after an inhibitory avoidance training. We found that ketamine enhances the early consolidation phase of aversive memory processing. Unpaired t test showed no significant difference between vehicle and ketamine groups injected immediately posttraining. Retention latencies were significantly longer in vehicle-treated rats than in control groups, indicating that rats correctly retained memory of the shock experience.
Rats retained memory of the shock experience when given ketamine immediately after training, but not 3-h after training.
3.2. Memory enhancing effects of immediate post-training ketamine injection are dependent on adrenal catecholamines
Ketamine, or its vehicle, was given to rats immediately after the inhibitory avoidance training to examine whether the memory enhancing effects were dependent on adrenal catecholamines. The results indicated that the anesthetic agent enhanced memory but not pre-existing behavioral differences among all experimental groups.
Rats treated with ketamine had longer retention latencies than rats treated with vehicle or sham ADMX. This indicates that a functional adrenal medulla is required for enhancing effects of ketamine on fear memory consolidation.
3.3. Memory enhancing effects of immediate post-training ketamine injection are dependent on β-adrenoceptor activation
In this experiment, rats were given immediate post-training injections of ketamine or its vehicle, 30 min before the inhibitory avoidance training. Ketamine and propranolol had no effect on training latencies, but the interaction between the two factors did. Post-hoc tests indicated that rats treated with ketamine alone had longer retention latencies than rats treated with vehicle or propranolol.
3.4. An intact locus coeruleus is required to enable memory enhancing effects of immediate post-training ketamine injection
To examine whether immediate posttraining ketamine anesthesia enhanced memory, rats received either temporary LC lesions with lidocaine or vehicle, and then were administered with ketamine. Average step-through latencies were 7.56 0.43 s for all groups, and ketamine did not affect training or retention latencies. Sham lesioned vehicle-treated rats retained memory of the shock experience for longer than sham lesioned vehicle-treated rats.
This experiment examined whether immediate post-training ketamine injection enhanced memory. It did not reveal any significant ketamine or propranolol treatment effects or an interaction between both factors. Rats given intra-BLA propranolol together with ketamine had longer retention latencies than those given vehicle alone, and rats given ketamine alone had longer retention latencies than those given vehicle alone and propranolol alone.
3.6. Memory enhancing effects of post-training ketamine injection are not influenced by anesthesia-induced sleep parameters
Studies have shown that sleep influences memory consolidation. We examined whether different experimental conditions affected memory retention.
Ketamine did not alter the sleep onset time or duration of rats given the anesthetic injection, and there was no significant correlation between sleep onset time or duration and 48-h retention latencies shown by all rats treated with ketamine.
- Discussion
Ketamine anesthesia enhances memory consolidation of fearful experiences when administered shortly after an inhibitory avoidance training via a combined peripheral and central sympathomimetic action. This action likely terminates with the activation of the BLA noradrenergic system.
Ketamine anesthesia modulates time-dependent processes of aversive memory consolidation and potentiates adrenergic/noradrenergic signaling to promote aversive memory retention. Adrenal medullectomy and blockade of ß-adrenoceptors with propranolol prevented the memory potentiating effects of ketamine.
Ketamine has been shown to have sympathomimetic effects, via inhibition of the noradrenaline transporter, at both the peripheral and central levels, or by increasing LC noradrenergic neuronal firing. This has been shown to influence fear memory consolidation.
Systemic adrenaline induces noradrenaline release within the brain, including the basal lateral awning (BLA). Adrenal medullectomy or central blockade of noradrenergic transmission prevents these effects. Ketamine, administered immediately after a trauma, potentiates memory consolidation for the traumatic event via activation of ß-adrenergic receptors in the BLA. This mechanism is similar to that of propofol, which enhances aversive memory consolidation only when given shortly after encoding.
Ketamine anesthesia did not influence sleep properties in our experiments, and the different conditions (adrenal medullectomy, LC lesion, systemic or intra-BLA injection of propranolol) had no influence on sleep onset and duration induced by ketamine.
Previous studies using sub-anesthetic doses of ketamine to examine the effects of ketamine on aversive memory processes have led to discrepant findings. However, one study in mice found that ketamine reduced freezing behavior one week prior to contextual fear conditioning. Ketamine is an N-methyl-d-aspartate (NMDA) receptors blocker and has been shown to be crucially involved in memory modulation processes. However, data regarding the impairing effect of MK-801 on aversive memory are still inconclusive.
One study showed that ketamine increased fear memory retention in rats, while another study found that ketamine did not prevent PTSD symptoms.
There is a general agreement in clinical studies that treatment with ketamine soon after accidental trauma is associated with increased symptoms of PTSD, while in humans it seems to be particularly effective in ameliorating comorbid depressive symptoms.
Ketamine has beneficial effects in patients suffering from PTSD, but may also contribute to the development of PTSD in patients at risk of developing PTSD. This may be because ketamine enhances memory consolidation and contributes to the development of PTSD later in life.
Our findings have a strong translational value for the management of ketamine anesthesia in emergency care and trauma victims, as they may help to prevent the development of trauma-related disorders later in life.
- Conclusions
Ketamine anesthesia enhances memory only when administered immediately after a traumatic event, and this effect is mediated by a combined peripheral-central potentiation of the sympathetic nervous system.
Author Contributions
MM designed the experiments, PCo performed the experiments, GFM, VDC and AP analyzed the data, and PCa wrote the manuscript.
Funding source
This work was supported by the Italian Ministry of Education MIUR and the Italian Ministry of Health.
Study details
Compounds studied
Ketamine
Topics studied
Neuroscience
Study characteristics
Animal Study
Participants
206