Identification of 5-HT_2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT_2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT_2A-Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT_2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT_2A-Gq but not 5-HT_2A-β-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT_2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT_2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT_2A agonists. We also demonstrate that β-arrestin-biased 5-HT_2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT_2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.