Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnrl) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnrl mediates fear inhibition, we hypothesize that a functional interaction between Cnrl and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BU6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear-or anxiety-like behaviors. Nonetheless, administration of a Cnrl antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnrl -positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnrl contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnrl CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.