Psilocybin Decreases Preference for Large Rewards Accompanied by Increased Activity of Parvalbumin Neurons With Perineuronal Nets in the Medial Prefrontal Cortex

Jun 2, 2026The European journal of neuroscience

Psilocybin reduces preference for big rewards while increasing activity of specific inhibitory neurons in the brain's decision-making area

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Abstract

A single dose of psilocybin decreased large reward choices in rats 48 hours after administration.

Psilocybin acutely increased head-twitch responses in male Long Evans rats.
Forty-eight hours post-injection, psilocybin reduced the number of choices for large rewards.
Latency to choose large rewards also increased after psilocybin treatment.
These changes in reward choice were not influenced by the delay in reward availability.
Psilocybin increased the density of neurons marked by perineuronal nets, parvalbumin, and c-Fos in the dorsomedial prefrontal cortex.
The findings indicate a potential mechanism where psilocybin may reduce motivation for immediate rewards through increased activity of specific interneurons.

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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-HTreceptors 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. 2A