Psilocybin decreases preference for large rewards accompanied by increased activity of parvalbumin neurons with perineuronal nets in the medial prefrontal cortex.
Jenna Houff, Andrew Williams, Obie Allen, Barbara Gisabella, Harry Pantazopoulos, Alberto Del Arco
Figshare March 11, 2026 preprint DOI: 10.6084/m9.figshare.31640851 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial |
|---|---|
| Population | Male Long Evans rats |
| Intervention | Psilocybin |
| Duration | 48 hours after injection |
| Topics | Psilocybin |
| Keywords | Prefrontal cortex Impulsivity Parvalbumin Inhibitory postsynaptic potential Gabaergic Premovement neuronal activity Perineuronal net Glutamatergic Somatosensory system Electrophysiology Temporal discounting Delay discounting Interneuron Glutamate receptor Cognition |
| Key findings | Psilocybin decreased large reward choices and increased latency to those choices 48 hours after administration, effects independent of delay and associated with increased activation of parvalbumin interneurons with perineuronal nets in the dorsomedial 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 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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |