Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors

Abstract

A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for posttraumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybins potential effect in fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybins effect on fear extinction are not understood. In this study, we used an auditory delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, though these changes were sensitive to dose. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drugs effects. Co-treatment with a 5-HT2A receptor antagonist blocked psilocybins effects for extinction, extinction retention and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybins ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.