With certain disorders, notably PTSD, the time of the insult that created the disorder is known—it is when the initiating trauma occurred. New preclinical approaches are examining mechanisms of consolidation of learning and how this consolidation process could be interrupted to prevent the development of trauma-related disorders.
Decades of preclinical research demonstrate that memories do not immediately become permanent at the time of the initial experience. Instead they exist in a labile state for at least hours and possibly days, during which they become consolidated into a more permanent memory (). There is a host of in vitro
and in vivo
data in animals outlining the molecular, synaptic, neurotransmitter and systems-level changes that may occur during this consolidation process80
. This literature suggests that during the immediate period after fear training in the animal model and after trauma in the human patient, it may be possible to disrupt the consolidation of new fear memories that are in the process of being formed65
Although there are philosophical and ethical questions raised by a potential amnestic agent that would ‘erase’ a memory fully, it is increasingly clear that differential memory systems are encoding different aspects of a memory in parallel. In other words, declarative or explicit memory systems involving hippocampal-cortical pathways are likely to be encoding the ‘what, when and where’ of an event, while in parallel, amygdala-cortical pathways are encoding the emotional salience and aversiveness of the memory. Therefore, agents that block the ‘emotional overconsolidation’ of a traumatic memory perhaps could preserve the declarative aspects of the same memory. This idealized approach would not render the patient fully amnestic, but would potentially prevent PTSD.
Many of the ideas on interruption of consolidation stem from a protocol called ‘avoidance learning’, in which an animal is conditioned in a box with two compartments. When it steps from one compartment to the next, it receives a mild footshock80
. After this training, the animal then avoids spending time in the compartment in which it was shocked, even if there are no more reinforcing shocks. Consolidation of contextual fear memory in this protocol is disrupted after training by a variety of agents, including dopaminergic, cholinergic and other modulatory drugs, but most notably those involving the adrenal stress system—epinephrine and glucocorticoids81,82
. Activation of the endogenous fight or flight adrenergic and glucocorticoid responses seems to be involved in strengthening these memories after the event. Notably, some of these manipulations do not impair consolidation of different types of memory, such as pavlovian fear conditioning, in contrast to their effects on consolidation of inhibitory avoidance learning. This difference in the animal models may have to do with the different neural circuits involved in cued fear conditioning and inhibitory avoidance learning.
Fear consolidation (at least with certain forms of fear training such as inhibitory avoidance learning) is blocked after training by an antagonist of noradrenergic activation. Propranolol, a common β-blocker used for hypertension, can block central β1
adrenergic receptors. Clinical trials are testing the use of propranolol to prevent the formation of PTSD after trauma. In one study, subjects who presented to an emergency room immediately after a traumatic event (primarily motor vehicle accidents)83
randomly received either propranolol or placebo, orally four times daily for 10 days, followed by a taper period. The first dose of medicine was administered, on average, 4 hours after the traumatic event. One month after the trauma, PTSD measures trended lower in the 11 completers who took propranolol compared to the 20 completers who did not. Also when exposed to script-driven mental imagery of the trauma, a significant number of those who took placebo had ongoing physiological symptoms of PTSD, whereas none of the subjects who took propranolol did. Given the length of time that subjects took propranolol, and given that only 1 or 2 doses would have occurred during the expected period of early memory consolidation, it is unclear whether these effects are due to ‘blockade of consolidation’ versus ‘prevention of stress sensitization’—another hypothesis of PTSD development—but the pilot data are intriguing.
A second open-label study examined 19 completers, 11 of whom took propranolol three times daily beginning 2–20 h after the trauma for 7 days followed by a taper period84
. At 2 months after trauma, levels of PTSD symptoms were significantly different in the subjects treated with propranolol. These studies were not blinded and had small numbers of subjects. Furthermore, given that propranolol is used frequently to treat hypertension and social anxiety disorder, significant amnestic properties might have been expected to be clinically obvious by now. Larger randomized clinical trials are ongoing to examine whether these promising pilot findings are robust and reproducible in a larger controlled and blinded design.
Another consolidation-blockade approach is based on the findings that lower cortisol levels after trauma predict subsequent PTSD85,86
. Combined with a large body of data that glucocorticoids are involved in emotional memory encoding and retrieval and that high doses of systemic glucocorticoids decrease the memory-enhancing effects of catecholamines87
, this finding indicates that glucocorticoids given after trauma may enhance normal stress responsiveness and prevent overconsolidation of trauma memories. Pilot data in humans support these hypotheses. Exogenously administered stress doses of cortisol reduced the development of subsequent PTSD in medical-surgical patients after septic shock88
. A randomized, double-blinded study replicated the finding with 11 patients that received placebo and 9 that received hydrocortisone for 6 days after septic shock. Thirty-one months later, significantly more subjects who had received placebo compared with hydrocortisone had PTSD symptoms from their intensive-care hospital experience88
. These studies also have small numbers of subjects, yet provide intriguing early data.
Giving corticosterone to rats following a reminder trial 24 h after fear conditioning89
indicates that enhanced glucocorticoid modulation may enhance the extinction component of fear, similarly to the mechanisms described above. However, the inverted ‘U’ relationship of the glucocorticoid system and the complexities of consolidation, extinction and reconsolidation make the story complicated. In a similar protocol, inactivating glucocorticoid receptors with an antagonist led to a disruption of memory retrieval when tested later90
. Although these results at first seem contradictory, they are consistent with the increasing data implying that every memory recall event is accompanied by competition between molecular events that strengthen the original memory (reconsolidation) and those that inhibit that memory (extinction)70
. By differentially enhancing or inhibiting these processes, opposing effects on the state of the existing fear memories may be obtained.
, including dopamine92
and glutamate-NMDA receptor activation93
, are implicated in the consolidation of fear memories. This work remains in its early stages, but there is room for optimism that a better understanding of the mechanisms of fear consolidation will lead to direct translational interventions that may one day prevent the development of anxiety disorders in acutely traumatized subjects and that psychopharmacological interventions in emergency rooms, on the battlefield or after a disaster may be as important in later PTSD prevention as early routine medical interventions after stroke and myocardial infarction are today.