A single dose of psilocybin produces rapid and sustained antidepressant-like effects in both healthy mice and mice exposed to chronic corticosterone, a model of stress. Psilocybin reversed stress-induced reductions in neuroplasticity within the prefrontal cortex and hippocampus, increasing dendritic branching, spine density, and levels of synaptic proteins (p-GluA1, PSD95, synapsin-1) and activating the BDNF-mTOR signaling pathway. It also promoted neurogenesis, as indicated by more DCX-positive cells. These findings suggest that psilocybin's antidepressant action is linked to its ability to enhance structural and molecular neuroplasticity.
Psilocybin rapidly reversed depressive-like behaviors in mice subjected to chronic restraint stress, an effect comparable to ketamine. Both drugs prevented stress-induced loss of astrocytes and reduced levels of the A1 astrocyte marker C3 protein in the prefrontal cortex. The active metabolite psilocin stimulated primary astrocyte activation, proliferation, and release of ATP, lactate, and glutamate, and improved mitochondrial function. Psilocin also reversed impairments caused by A1 astrocytes. Depleting astrocytes in the prelimbic region of the medial prefrontal cortex diminished psilocybin's antidepressant action in unstressed mice, suggesting astrocytes play a key role in the drug's effects.