Psilocybin decreases preference for large rewards accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex.

Clinical trials suggest that a single dose of psilocybin may be an effective treatment for substance use disorders. Choice impulsivity is a value-based decision-making bias that predicts drug-intake escalation and is commonly associated with substance use disorders. The dorsomedial prefrontal cortex regulates choice impulsivity and is enriched with 5-HT2A receptors that mediate effects of psilocybin. We hypothesized that psilocybin has long-term (≥48 hours) effects on choice impulsivity in association with dorsomedial prefrontal cortex inhibitory interneurons with perineuronal nets (PNNs). Male Long Evans rats were trained in a delay discounting task where rats chose between delayed large rewards and immediate small rewards. 48 hours after psilocybin or vehicle injections, delay discounting 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 large reward choices and increased the latency to large reward 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 triple-labelled neurons (PNN+PV+cFos) in the dorsomedial prefrontal cortex. These results suggest that psilocybin decreases appetitive motivation through the increased activation of PV interneurons with PNNs in the dorsomedial prefrontal cortex.