Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia
James J Gattuso, Ahmed Kamal, Jennyfer M. Payet, Kato Havaux, Jenna Hendey, Bilgenur Bezcioglu, Zoe J. Phelan, Maddy Orchard, Divyesh Bhanot, Matthew W. Hale, Anthony J. Hannan, Thibault Renoir
Neuropsychopharmacology July 18, 2026 DOI: 10.1038/s41386-026-02501-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using knockout mouse model Peer reviewed |
|---|---|
| Population | Metabotropic glutamate receptor 5 (mGlu5) knockout and wild-type mice |
| Intervention | Psilocybin |
| Dose | 1 mg/kg, intraperitoneal |
| Duration | Nine-day follow-up after treatment |
| Topics | Psilocybin Serotonin |
| Keywords | Prepulse inhibition Hallucinogen Knockout mouse Schizophrenia object-oriented programming Metabotropic receptor Sertindole Glutamatergic Pharmacology Psychosis Metabotropic glutamate receptor |
| Key findings | Disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. |
Abstract
Abstract Psilocybin is a serotonergic psychedelic drug with emerging therapeutic applications, yet its actions under glutamatergic dysfunction, and relevance to schizophrenia and associated psychiatric disorders, remain unclear. We examined the acute and long-lasting effects of psilocybin (1 mg/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT 2A receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light–dark box and increased immobility time in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic–serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.
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 39
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science December 10, 2020
- Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies Journal of Psychopharmacology September 20, 2010
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
and 34 more in the library