Psilocybin decreases reward-seeking behavior 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
bioRxiv (Cold Spring Harbor Laboratory) December 26, 2025 preprint DOI: 10.64898/2025.12.22.696123 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male Long Evans rats |
| Intervention | Psilocybin |
| Duration | 48 hours |
| Topics | Psilocybin |
| Keywords | Parvalbumin Impulsivity Prefrontal cortex Inhibitory postsynaptic potential Hallucinogen Perineuronal net Premovement neuronal activity Somatosensory system Electrophysiology Gabaergic Extracellular |
| Key findings | Psilocybin decreased choices of larger delayed rewards and increased activation of parvalbumin interneurons with perineuronal nets in the dorsomedial prefrontal cortex, suggesting reduced reward seeking rather than altered impulsivity. |
Abstract
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.
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 |
Citations in the library
Cites 34
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Long-term follow-up of psilocybin-facilitated smoking cessation The American Journal of Drug and Alcohol Abuse July 21, 2016
- Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder JAMA Psychiatry August 24, 2022
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 29 more in the library