Serotonin 5-HT2A receptor density in the prefrontal cortex of people with schizophrenia depends on which radiotracer is used to measure it, because different tracers bind different receptor conformations. Using the inverse agonist [18F]altanserin, receptor density appeared decreased; using the agonist [3H]LSD, it appeared increased; and using the antagonist [3H]MDL100907, it was unchanged. These differences were more pronounced in schizophrenia subjects who were antipsychotic-free at death. The findings suggest a shift toward the active functional conformation of the 5-HT2A receptor in schizophrenia, consistent with increased cortical serotonin 2A receptor activity.
In a mouse model of chronic unpredictable mild stress, two doses of psilocybin (1 mg/kg, given 7 days apart) reversed stress-induced anhedonia and behavioral despair, but not apathy-related behavior. Psilocybin also produced an anxiolytic-like effect. However, it did not reverse stress-induced physiological signs of a hyperactive HPA axis or restore decreased brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Psilocybin increased expression and function of serotonin-2A receptors in the cortex of both control and stressed mice, and selectively increased glucocorticoid receptor expression in the cortex of stressed mice. These findings suggest psilocybin can rescue certain depressive and anxiety-like behaviors without normalizing all stress-related physiological or neuroplasticity impairments.