Koester, A. M. | Search bioRxiv

bioRxiv2024

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

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.

neuroscience↗

bioRxiv2021

EFR3 and phosphatidylinositol 4-kinase IIIα regulate insulin-stimulated glucose transport and GLUT4 dispersal in 3T3-L1 adipocytes.

Insulin stimulates glucose transport in muscle and adipocytes. This is achieved by regulated delivery of intracellular glucose transporter (GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, resulting in increased cell surface GLUT4 levels. Recent work identified a potential further regulatory step, in which insulin increases the dispersal of GLUT4 in the plasma membrane away from the sites of vesicle fusion. EFR3 is a scaffold protein that facilitates localisation of phosphatidylinositol 4-kinase type III to the cell surface. Here we show that knockdown of EFR3 or phosphatidylinositol 4-kinase type III impairs insulin-stimulated glucose transport in adipocytes. Using direct stochastic reconstruction microscopy, we also show that EFR3 knockdown impairs insulin stimulated GLUT4 dispersal in the plasma membrane. We propose that EFR3 plays a previously unidentified role in controlling insulin-stimulated glucose transport by facilitating dispersal of GLUT4 within the plasma membrane.

cell biology↗