CANNABINOID TYPE-1 RECEPTORS IN ACQUISITION/EXPRESSION OF PTSD-LIKE MEMORIES

Traumatic episodes can lead to stress-related conditions, such as post-traumatic stress disorders (PTSD), characterized by pathological fear memories. Amongst the numerous modulators of fear memory, the endocannabinoid system (ECS) and especially the cannabinoid type-1 receptors (CB1R) play a key role in aversive memory regulation suggesting that their modulation might impact PTSD development. CB1R were initially shown as necessary for fear extinction, although dispensable for the acquisition and consolidation of physiological fear memories. As fear extinction is dramatically impaired in PTSD, most studies dealing with the potential ECS role in this pathology have, therefore, focused on this fear memory processing phase. Unfortunately, after the first hopes for a therapeutic role of ECS signaling in PTSD, clinical trials manipulating CB1R activity have led to discrepant and generally inconclusive results. However, it is now clear that fear extinction impairment in PTSD is likely a consequence of pathological qualitative alterations in memory formation at the moment of trauma. Thus, fundamental differences exist between physiological and PTSD-like fear memory. Recently, a mouse model was developed, recapitulating key PTSD features. Fear conditioning of mice in a specific context followed by glucocorticoid administration induces: (i) traumatic hypermnesia, exaggerated fear responses to trauma-associated cues and (ii) contextual amnesia memory deficit for the predictive context. Using this model, we identified a pivotal role of CB1R in the PTSD-like fear memory alteration in mice and investigated their subcellular, cellular and brain region location. Finally, we also investigated the putative therapeutic potential of their targeting through pharmacological modulation.