Psychedelic compounds directly excite 5-HT 2A Layer 5 Pyramidal Neurons in the Prefrontal Cortex through a 5-HT 2A Gq -mediated activation mechanism
OpenAlex – November 15, 2022
Source: OpenAlex
Summary
A compelling neuroscience finding reveals psilocin, a serotonergic psychedelic, powerfully increases firing in all identified serotonin 5-HT2A receptor neurons within the prefrontal cortex. Utilizing electrophysiology and biochemical analysis, 10 μM psilocin acted as an agonist, influencing neurotransmission. This provides critical insight for psychedelics and drug studies, impacting brain regions like the infralimbic cortex. The chemistry and biophysics of these receptor interactions are key to understanding psilocin's effects and neurotransmitter receptor influence on behavior.
Abstract
Summary Psilocin, the active compound in Psilocybe sp . mushrooms, is a serotonergic psychedelic that has recently gained renewed interest due to its potential as a therapeutic tool. Despite promising clinical findings, the underlying signaling mechanisms and brain region-specific effects of psilocin and other psychedelic drugs remain unclear. Psilocin, like other psychedelic compounds, is an agonist at many serotonin and other biogenic amine receptors; however, activation of serotonin (5-Hydroxytryptamine, or 5-HT) 2A receptors (5-HT 2A Rs) is understood as the main molecular target for the psychoactive effects in animals and humans. 5-HT 2A Rs are abundantly expressed in the prefrontal cortex (PFC); however, the biochemical actions of psilocin on PFC neurons remain poorly understood. In this study, we used in vitro slice electrophysiology to examine how psilocin acutely alters the activity and electrophysiological properties of layer 5 pyramidal neurons in the mouse PFC. Focal application of psilocin (10 μ M) onto nonspecified Layer 5 Pyramidal neurons in the prelimbic PFC of C57BL/6J mice produced variable effects on firing (increase, decrease, or no change). 5-HT 2A R layer 5 pyramidal neurons in the mouse prelimbic PFC were identified via labeling in a 5-HT2A-ERT2-Cre mouse crossed with an Ai9 tdTomato reporter. Focal application of psilocin increased firing in all identified 5-HT 2A R neurons but did not result in any significant changes in synaptic transmission. Overall, the results demonstrate that psilocin evokes strong firing changes in the PFC that are 5-HT 2A R and G α q dependent, thereby providing valuable insights into the effects of psilocin on a brain region implicated in mediating psychedelic drug actions.