An exploration of the relationships between the effects of psilocybin on behavior, 5-HT_2A receptor occupancy, and...

Psilocybin has shown rapid and sustained antidepressant effects in patients with major depressive disorder, yet the neurobiological mechanisms underlying these outcomes remain unclear.

This study aimed to bridge clinical and preclinical findings by investigating the relationships between 5-HT_2A receptor occupancy (RO) achieved after administration of psilocybin and its effects on behavior and markers of neuroplasticity in mice.

In vivo 5-HT_2A RO was determined via displacement of [³H]MDL-100,907 in the prefrontal cortex (PFC). To relate RO with behavioral outcomes of psilocybin, we assessed the head twitch response (HTR) acutely and investigated behavior in the elevated zero maze (EZM) and forced swim test (FST) 20-24 hours post-drug. Neuroplastic changes were assessed by measuring α-tubulin post-translational modifications (PTMs) and expression of key synaptic proteins in both the PFC and amygdala.

Psilocybin produced dose-dependent 5-HT_2A RO (RO₅₀ = 0.88 mg/kg) and an inverted-U dose-response in HTR, with peak effects occurring between ~44% and 62% RO. Behaviorally, a 1.5 mg/kg dose increased the open areas ratio in the EZM, while 3 mg/kg reduced immobility in the FST, 20 and 24 hours after dosing, respectively. Both dose levels shifted α-tubulin PTMs toward a more dynamic microtubule state and selectively increased synaptic marker expression in the PFC, not in the amygdala.

These findings suggest that the therapeutic effects of psilocybin could be mediated by dose- and region-specific enhancement of neuronal plasticity, with distinct signatures associated with anxiolytic-like and antidepressant-like properties.