Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms

Psilocin, the active metabolite of psilocybin, induces a long-lasting decrease in excitatory synaptic strength in the prefrontal cortex of rats, an effect that is independent of sex. This synaptic depression originates presynaptically and is not mediated by 5-HT2A or metabotropic glutamate group 2 receptors, but instead involves enhanced GABAergic inhibition. The effect is partially blocked by a 5-HT1A receptor antagonist and fully blocked by a TrkB receptor antagonist. These sustained changes in synaptic activity may relate to reduced prefrontal connectivity observed in humans and could affect cognitive function.

Study at a glance

Abstract

Psilocybin is a naturally occurring psychedelic compound with potential antidepressant effects. Although it has long been used by humans, primarily for recreational purposes, the molecular mechanisms underlying its actions remain incompletely understood. Here, we examined the acute effects of psilocin, the active metabolite of psilocybin, on excitatory neurotransmission in the prefrontal cortex (PFC). Slice electrophysiological whole-cell and field potential recordings were conducted in the rat prelimbic cortex during bath application of psilocin. We observed a sex-independent long-term synaptic depression (LTD) of presynaptic origin. This effect was independent of 5-HT2A and metabotropic glutamatergic receptor group 2 and mediated through enhanced GABAergic tone. The effect was partially inhibited by 5-HT1A receptor antagonist and completely blocked in slices pre-treated with the neuronal receptor tyrosine kinase 2 (TrkB) receptor antagonist ANA-12. These findings suggest that psilocin exerts a complex modulatory influence on excitatory neurotransmission in the prelimbic PFC, involving GABAergic and serotonergic interactions, and producing sustained alterations in synaptic activity that persist beyond drug exposure. Psilocin-induced LTD, independent of 5-HT2A receptor activation, may be associated with the reduced prefrontal connectivity reported in humans after psilocin administration and could have implications for cognitive function.