The Medial Prefrontal Cortex Modulates Psychedelic-like Effects of Psilocin
ACS Pharmacology & Translational Science – July 08, 2025
Source: OpenAlex
Summary
A breakthrough in **Neuroscience** reveals the **prefrontal cortex** critically regulates **psychedelic** effects. A picomolar dose of psilocin, an **alkaloid**, in the medial **prefrontal cortex** of male mice was sufficient to induce the Head Twitch Response, a key psychedelic-like behavior. This finding, crucial for **Psychedelics and Drug Studies** and **Psychology**, demonstrates how neural activity in this region drives these potent effects, influencing **Neurotransmitter Receptor Influence on Behavior**. Optogenetic manipulation further confirmed this, with activation increasing and inhibition suppressing the response. This **Neuroscience** insight promises safer therapeutic applications.
Abstract
Recent advancements in the study of psilocybin and its active metabolite psilocin have highlighted their unique psychedelic properties and potential therapeutic applications, particularly in the rapid and sustained treatment of depression. However, the potent acute psychedelic effects of psilocybin necessitate a deeper understanding of the neural mechanisms underlying its action. In this study, we investigated the psilocin-induced neural activity in male mice using c-Fos immunofluorescent labeling and identified brain regions associated with psychedelic-like activity. Among the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and dorsomedial striatum (DMS), only the mPFC was specifically associated with the head twitch response (HTR), a hallmark of psychedelic-like behavior. A picomolar dose of psilocin in the mPFC was sufficient to induce significant HTR, suggesting that c-Fos-positive neurons in this region modulate psychedelic-like activity. To validate this hypothesis, optogenetic activation of these neurons significantly increased spontaneous HTR in TRAP2 mice, whereas acute inhibition suppressed drug-induced HTR. These findings establish the mPFC as a critical regulator of psilocin-induced psychedelic-like activity and provide valuable insights for enhancing the clinical safety and therapeutic application of psychedelics.