Psilocybin Decreases Preference for Large Rewards 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 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 h) 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. Forty-eight 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 h 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.