Extending these findings and demonstrating a role for ECBs in fear extinction, Marsicano and colleagues reported elevated AEA and 2-AG BLA levels after extinction training in mice [86], and produced impairments in extinction learning (but not fear conditioning) by CB1R KO or systemic antagonist (SR141716A) administration [28,86] (for studies reporting similar effects, see [87–89]). Subsequent studies showed that infusing SR141716A directly into the BLA (or mPFC [90]) was sufficient to impair a cued fear extinction in rats [91,92]. Some authors have posited that these effects on extinction reflect a more general role of ECBs in promoting the long-term adaptation to aversion situations [47,93,94]. The ability of ECBs to modulate fear extinction is bidirectional. Activating CB1R via systemic or intra-hippocampal or -mPFC administration of either the CB1R agonist, WIN55212-2, the ECB reuptake blocker, AM404, or AEA itself has been shown to facilitate rodent fear extinction, in most cases without affecting conditioned fear [89,95–98] (but see [90]). Initial work has found that similar effects can be produced in humans by administering THC [99].
