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 (CB1)-deficient mice (CB1-/-) and their wild-type littermates (CB1+/+) to footshocks of different intensities. Only application of an intense footshock resulted in a sustained fear response to the tone in CB1-/-. Using the intense protocol, we next investigated whether endocannabinoids mediate their effects via an interplay with corticotropin-releasing hormone (CRH) signaling. Pharmacological blockade of CB1 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 CB1. As CRHR1(-/-) are known to be severely impaired in stress-induced corticosterone secretion, our observation also implicates that corticosterone is dispensable for CB1-mediated acute fear adaptation. Instead, conditional mutants with a specific deletion of CB1 in principal neurons of the forebrain (CaMK-CB1-/-), or in cortical glutamatergic neurons (Glu-CB1-/-), showed a similar phenotype as CB1-/-, thus indicating that endocannabinoid-controlled glutamatergic transmission plays an essential role in acute fear adaptation.