Psilocybin's active metabolite psilocin increases activity in the medial prefrontal cortex (mPFC), a brain region rich in 5-HT2A receptors. A specific population of neurons in the prelimbic/anterior cingulate mPFC that express these receptors becomes more excitable and fires more in response to psilocin and a selective 5-HT2A receptor compound, effects dependent on both the receptor and Gα q signaling. A novel non-hallucinogenic psychedelic compound produced similar effects. These results point to membrane-bound 5-HT2A receptors and intracellular Gα q signaling as potential therapeutic targets for psychedelic-associated plasticity.
Psilocin, the active metabolite of psilocybin, acutely reduced voluntary ethanol consumption in mice exposed to two models of chronic ethanol exposure without altering locomotor behavior. It increased activation of the central amygdala (CeA) and decreased relative activation of corticotropin-releasing factor type 1 (CRF1) receptors in CeA subregions of ethanol-naive female mice, with similar effects observed in chronic ethanol-exposed mice at 24 and 72 hours of withdrawal. Psilocin also elevated corticosterone levels at 24 hours but not at 72 hours of withdrawal. These findings indicate that psilocin engages CeA circuitry and reduces relative CRF1 activation alongside acute reductions in drinking, helping explain potential therapeutic mechanisms for alcohol use disorder.