Psychedelic drugs such as LSD and psilocybin show promise as treatments for depression, anxiety, PTSD, migraine, and cluster headaches by activating the 5-HT2A receptor (HTR2A). Researchers engineered several new mouse lines to study the role of HTR2A and the neurons that express it. One line allows visualization of the receptor and identification of HTR2A-containing cells, providing a detailed anatomical map. Another line has a humanized version of the receptor, and a third enables targeted genetic manipulation. The mice exhibited expected behavioral responses to psychedelics, confirming their usefulness. Electrophysiology showed that serotonin increases firing of specific pyramidal neurons through HTR2A, consistent with the receptor's location on the cell surface. These tools will help clarify how psychedelics work at molecular, cellular, and behavioral levels.
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.