Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice

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.

Study at a glance

Abstract

Background: Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert their effects. However, the mechanisms underlying this action of psilocybin have not been identified. Aims: To investigate whether psilocybin has rapid and sustained antidepressant-like effects in mice and investigate whether its potential mechanisms of action are related to promoted neuroplasticity. Methods: We first examined the antidepressant-like effects of psilocybin in normal mice by the forced swimming test and in chronic corticosterone (CORT)-exposed mice by the sucrose preference test and novelty-suppressed feeding test. Furthermore, to explore the role of neuroplasticity in mediating the antidepressant-like effects of psilocybin, we measured structural neuroplasticity and neuroplasticity-associated protein levels in the prefrontal cortex (PFC) and hippocampus. Results: We observed that a single dose of psilocybin had rapid and sustained antidepressant-like effects in both healthy mice and chronic CORT-exposed mice. Moreover, psilocybin ameliorated chronic CORT exposure-induced inhibition of neuroplasticity in the PFC and hippocampus, including by increasing neuroplasticity (total number of dendritic branches and dendritic spine density), synaptic protein (p-GluA1, PSD95 and synapsin-1) levels, BDNF-mTOR signalling pathway activation (BDNF, TrkB and mTOR levels), and promoting neurogenesis (number of DCX-positive cells). Conclusions: Our results demonstrate that psilocybin elicits robust, rapid and sustained antidepressant-like effects which is accompanied by the promotion of neuroplasticity in the PFC and hippocampus.