In a mouse model of schizophrenia lacking the metabotropic glutamate receptor 5 (mGlu5), psilocybin (1 mg/kg) caused hyperlocomotion, while normal mice showed no such effect. Male knockout mice also had a stronger head-twitch response, indicating enhanced serotonin 2A receptor signaling. Psilocybin increased neural activity in the claustrum of normal but not knockout mice, showing that intact mGlu5 signaling is needed for this effect. Psilocybin did not change anxiety-like behavior but increased immobility in a stress test. Notably, it produced a sustained normalization of sensorimotor gating in female knockout mice nine days after treatment, suggesting sex-dependent long-term effects.
Acute psilocybin reduced compulsive grooming in male mice for up to one week and in both sexes shortly after dosing, but chronic psilocybin did not improve anxiety-like, depressive-like, or compulsive-like behaviors or social deficits. The findings suggest acute psilocybin may help reduce compulsive behaviors, while repeated low-dose use offers limited benefits. The study used SAPAP3 knockout mice, a model of obsessive-compulsive disorder, and found differences in serotonin receptor signaling between genotypes. Results highlight the need for caution as psychedelic-assisted therapy gains approval, especially regarding microdosing.