MYCOLab Ai Logo - gold and army green

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

Summary

Scientists discovered that psychedelic drugs work by activating a specific signaling pathway in the brain called the 5-HT2A-Gq pathway. By creating new drug-like molecules, they found that drugs need to strongly activate this particular pathway to produce psychedelic effects like hallucinations. This discovery could help researchers design new psychiatric medicines that have therapeutic benefits without the hallucinogenic side effects that worry doctors and patients.

Background

Serotonergic psychedelics show considerable therapeutic potential, with 5-HT2A receptor activation mediating psychedelic effects. However, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles in psychedelic activity unclear.

Objective

To determine which 5-HT2A receptor signaling pathways mediate psychedelic potential by developing selective 5-HT2A ligands with varying Gq efficacies and β-arrestin-biased ligands, and testing their effects using head-twitch response in mice.

Results

5-HT2A-Gq but not β-arrestin2 recruitment efficacy predicts psychedelic potential, with a threshold of approximately 70% Gq efficacy required for head-twitch response. β-arrestin-biased 5-HT2A agonists blocked psychedelic effects and induced receptor downregulation. Disrupting Gq-PLC signaling attenuated the head-twitch response, confirming pathway involvement.

Conclusion

5-HT2A receptor Gq-signaling efficacy can be fine-tuned to generate ligands distinct from classical psychedelics. Understanding this threshold mechanism permits rational development of non-psychedelic 5-HT2A agonists with potential therapeutic applications while minimizing hallucinogenic side effects.
  • Published in:Nature Communications,
  • Study Type:Preclinical Research,
  • Source: PMID: 38102107, DOI: 10.1038/s41467-023-44016-1
Scroll to Top