Fear relief-toward a new conceptual frame work and what endocannabinoids gotta do with it.

The endocannabinoid system seems to play very specific roles in fear extinction, which can only be described within a well-defined model of the various fear relief processes. We, therefore, seek to clarify the current conceptual framework of fear relief within classical and operant fear conditioning paradigms as well as propose new clarifications within this framework where necessary. Based on these revisions as well as previous research involving the endocannabinoid system and fear relief, we are able to pinpoint the processes in which endocannabinoids seem to play a significant role. Following auditory-cued fear conditioning, this applies in particular to habituation and its involvement in acute and long-lasting fear relief. Following contextual conditioning, in contrast, endocannabinoids seem to affect relearning processes as well. Furthermore, we describe how the involvement of the endocannabinoid system develops over the course of the fear relief process and what this may imply for the clinical use of pharmacotherapies targeting the endocannabinoid system in treating fear and anxiety disorders.

Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling.

Recent evidence showed that the endocannabinoid system plays an important role in the behavioral adaptation of stress and fear responses. In this study, we chose a behavioral paradigm that includes criteria of both fear and stress responses to assess whether the involvement of endocannabinoids in these two processes rely on common mechanisms. To this end, we delivered a footshock and measured the fear response to a subsequently presented novel tone stimulus. First, we exposed different groups of cannabinoid receptor type 1 (CB(1))-deficient mice (CB(1) (-/-)) and their wild-type littermates (CB(1) (+/+)) to footshocks of different intensities. Only application of an intense footshock resulted in a sustained fear response to the tone in CB(1) (-/-). Using the intense protocol, we next investigated whether endocannabinoids mediate their effects via an interplay with corticotropin-releasing hormone (CRH) signaling. Pharmacological blockade of CB(1) receptors by rimonabant in mice deficient for the CRH receptor type 1 (CRHR1(-/-)) or type 2 (CRHR2(-/-)), and in respective wild-type littermates, resulted in a sustained fear response in all genotypes. This suggests that CRH is not involved in the fear-alleviating effects of CB(1). As CRHR1(-/-) are known to be severely impaired in stress-induced corticosterone secretion, our observation also implicates that corticosterone is dispensable for CB(1)-mediated acute fear adaptation. Instead, conditional mutants with a specific deletion of CB(1) in principal neurons of the forebrain (CaMK-CB(1) (-/-)), or in cortical glutamatergic neurons (Glu-CB(1) (-/-)), showed a similar phenotype as CB(1) (-/-), thus indicating that endocannabinoid-controlled glutamatergic transmission plays an essential role in acute fear adaptation.