Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.02.130419v1?rss=1 Authors: Higginbotham, J. A., Wang, R., Richardson, B. D., Shiina, H., Tan, S. M., Presker, M. A., Rossi, D. J., Fuchs, R. A. Abstract: Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental rat model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, I.P.) during memory reconsolidation alters (a) subsequent drug context-induced cocaine-seeking behavior, as well as (b) cellular adaptations and (c) excitatory synaptic physiology in the basolateral amygdala (BLA). Systemic CB1R antagonism - during, but not after, cocaine-memory reconsolidation - reduced drug context-induced cocaine-seeking behavior three days, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene expression and changes in BLA -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous excitatory post-synaptic current frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA during cocaine-memory reconsolidation, thereby facilitating cocaine-memory maintenance. These findings identify the CB1R as a potential therapeutic target for relapse prevention. Copy rights belong to original authors. Visit the link for more info