Psilocybin decreases reward-seeking behavior accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex

ABSTRACT Clinical trials suggest that a single dose of psilocybin is an effective treatment for substance use disorders (SUDs). Choice impulsivity is a value-based decision-making bias that predicts drug-intake escalation and is commonly associated with SUDs. The dorsomedial prefrontal cortex (dmPFC) regulates choice impulsivity and is enriched with 5-HT 2A receptors that mediate effects of psilocybin. We hypothesized that psilocybin has long-term (≥48 hours) effects on choice impulsivity in association with dmPFC inhibitory interneurons with perineuronal nets (PNNs). Male Long Evans rats were trained in a delay discounting task (DDT) where rats chose between delayed large rewards (LR) and immediate small rewards (SR). 48 hours after psilocybin or vehicle injections, DDT was assessed, and rats’ brains processed for microscopy analysis of extracellular matrix (PNNs) together with inhibitory parvalbumin (PV) interneurons and c-fos as a marker of neuronal activity. Psilocybin acutely increased head-twitch responses. Psilocybin decreased LR choices and increased the latency to LR choices 48 hours after administration. These effects were independent of delay and therefore not consistent with changes in impulsivity. Psilocybin also increased the density of PNN+PV+cFos triple-labeled neurons in the dmPFC. These results suggest that psilocybin decreases reward seeking through the increased activation of dmPFC PV interneurons with PNNs.