Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential.
Jason Wallach, Andrew B. Cao, Maggie M. Calkins, Andrew J. Heim, Janelle K. Lanham, Emma M. Bonniwell, Joseph J. Hennessey, Hailey A. Bock, Emilie I. Anderson, Alexander M. Sherwood, Hamilton Morris, Robbin De Klein, Adam K. Klein, Bruna Cuccurazzu, James Gamrat, Tilka Fannana, Randy Zauhar, Adam L. Halberstadt, John D. Mccorvy
Nature Communications December 15, 2023 DOI: 10.1038/s41467-023-44016-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Intervention | including β-arrestin-biased ligands |
| Topics | Serotonin |
| Keywords | Psychedelics Hallucinogens Psychoactive compounds Mind-altering substances Brain chemistry Neurobiology Brain research Molecular signaling Psychopharmacology Drug research Drug discovery Receptor interaction Therapeutics Drug development Medical treatments Non-hallucinogenic therapies Novel therapies |
| Citations | 153 |
| Key findings | 5-HT2A-Gq signaling efficacy, not β-arrestin2 recruitment, predicts psychedelic potential in male mice, and β-arrestin-biased agonists can block psychedelic effects. |
Abstract
Abstract 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 transducers, making their respective roles unclear. To elucidate this, we develop 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 recruitment 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 block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT 2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 137
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron July 15, 2025
- Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential Proceedings of the National Academy of Sciences April 14, 2025
- The structural diversity of psychedelic drug actions revealed. Nature Communications March 19, 2025
- Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited. ACS Pharmacology & Translational Science March 8, 2024
and 132 more in the library
Cites 35
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- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & Therapeutics May 1, 2019
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 30 more in the library