Neuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyJul 18, 2026

Psilocybin causes stronger immediate effects and sex-specific long-term improvements in sensory processing in a mouse model of schizophrenia lacking mGlu5

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 19, 2026

Abstract

Psilocybin induced hyperlocomotion in metabotropic glutamate receptor 5 knockout mice but not in wild-type mice.

The mGlu5 knockout mice exhibited an enhanced head-twitch response following psilocybin administration, indicating altered serotonergic signaling.
Acute psilocybin treatment increased c-Fos expression in the claustrum of wild-type mice, suggesting that functioning mGlu5 signaling is necessary for this response.
Psilocybin did not change anxiety-like behavior in the light-dark box or increase mobility in the Porsolt test.
Female mGlu5 knockout mice showed a lasting normalization in prepulse inhibition, a measure of sensorimotor gating, nine days post-treatment.
Disrupted mGlu5 signaling may amplify acute psilocybin responses and cause sex-dependent long-term effects on sensorimotor processing.

Simplified

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.