Cellular rules underlying psychedelic control of prefrontal pyramidal neurons
bioRxiv (Cold Spring Harbor Laboratory) October 23, 2023 Tyler G. Ekins, Isla Brooks, Sameer Kailasa et al. 17 citations preprint
Classic psychedelic drugs, such as LSD and psilocybin, are thought to boost brain cell activity in the prefrontal cortex by activating serotonin 2A receptors. However, this research shows that these drugs actually suppress the intrinsic excitability of pyramidal neurons in a dose-dependent manner. The suppression is stronger when drugs are applied outside cells than inside, and it occurs through a previously unknown mechanism: enhancement of potassium M-current channels, independent of serotonin 2A receptor activation. Computer models reveal that M-current activation interacts with other mechanisms to reduce excitability and shorten working memory span. This suggests psychedelics may trigger widespread homeostatic adjustments that contribute to therapeutic benefits.