Endocannabinoid interactions in the regulation of acquisition of contextual conditioned fear

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

The effects of anandamide signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats

RATIONALE: Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids. OBJECTIVES: Here, we tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles. METHODS: Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. RESULTS: Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions. CONCLUSIONS: URB597 treatment-induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Albeit further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable