Fear relief is neither sufficient nor essential for long-term fear extinction

Phobias are the most common form of anxiety disorders. They are characterized by irrational, intense and persistent fear of situations, activities, objects, animals or people. Exposure-based therapies turned out to be most efficient for the treatment of phobias. Fear conditioning and fear extinction are explicit animal models of phobias and exposure therapy, respectively. It is generally believed that fear relief upon confrontation with the fear eliciting situation/stimuli plays an essential role for the development of long-lasting changes in fear susceptibility. Here we challenge this view by demonstrating in cannabinoid receptor type 1 (CB1) knock-out mice – subdued to massed or spaced extinction training over the course of several days – that fear relief is neither sufficient nor essential for long-term fear extinction. In fact, CB1 knock-out mice showed sustained fear responses during a given extinction session but reduced fear from day to day, an effect which could be mimicked in wild-type mice by pharmacological blockade of CB1 receptors. Our data suggest that the treatment of anxiety disorders associated with exaggerated fear responses would benefit from a pharmacological exploitation of the endocannabinoid system in that potentiation of CB1 receptor signalling is expected to promote acute fear relief, even though long-term fear adaptation might be unaffected.