Psilocin mediates long-term synaptic depression in the prelimbic cortex through 5-HT2A receptor-independent mechanisms
Neuropharmacology – January 21, 2026
Source: OpenAlex
Summary
Psilocin, psilocybin's active form, profoundly alters brain chemistry. Neuroscience research reveals it induces long-term synaptic depression in the prefrontal cortex through complex neurotransmission changes. Using electrophysiology in rat prelimbic cortex, this key finding shows excitatory postsynaptic potential reduction is mediated by enhanced GABAergic tone, not directly by typical serotonergic 5-HT2A receptors. Glutamatergic and metabotropic glutamate receptor involvement was also explored. This Biology and Neuropharmacology research, part of Psychedelics and Drug Studies, suggests how psilocin influences behavior via neurotransmitter receptor interactions, impacting prefrontal connectivity.
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.