LAUSR

&NA; Endocannabinoids (eCBs) anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) were shown to be involved in the basis of trauma‐induced behavioral changes, particularly contextual conditioned fear, however, their ligand‐specific effects and possible interactions are poorly understood. Here we assessed specific eCB effects and interactions on acquisition of contextual conditioned fear employing electric footshocks in a rat model. We selectively increased eCB levels by pharmacological blockade of the degrading enzymes of AEA by URB597 and 2‐AG by JZL184 before traumatization either systemically or locally in relevant brain areas, the prelimbic cortex (PrL), ventral hippocampus (vHC) and basolateral amygdala (BLA). Following traumatization, a series of contextual reminders were conducted during which conditioned fear was assessed. While systemic URB597‐treatment during traumatization only slightly enhanced the acquisition of contextual conditioned fear, administration of the compound in the PrL and vHC led to the acquisition of stable, lasting conditioned fear, resistant to extinction. These effects of URB597 were blocked by simultaneous administration of JZL184. Similar treatment effects did not occur in the BLA. Treatment effects were not secondary to alterations in locomotor activity or nociception. Our findings suggest that AEA and 2‐AG functionally interact in the regulation of acquisition of contextual conditioned fear. AEA signaling in the PrL and vHC is a crucial promoter of fear acquisition while 2‐AG potentially modulates this effect. The lack of eCB effects in the BLA suggests functional specificity of eCBs at distinct brain sites. Graphical abstract Figure. No caption available. HighlightsEndocannabinoids interact in the regulation of conditioned fear acquisition.Prelimbic and ventral hippocampal anandamide signaling promotes acquisition.2‐arachidonoylglycerol blocks the effect of anandamide without effects per se.Basolateral amygdalar endocannabinoids do not alter conditioned fear acquisition.