Identification of 5-HT 2A Receptor Signaling Pathways Responsible for 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
bioRxiv (Cold Spring Harbor Laboratory) July 31, 2023 preprint DOI: 10.1101/2023.07.29.551106 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Male mice |
| Intervention | including β-arrestin-biased ligands |
| Topics | Serotonin |
| Keywords | Arrestin 5-HT Receptor Signal transduction Tachyphylaxis Pharmacology G protein-coupled receptor Cell biology Biochemistry |
| Citations | 11 |
| Key findings | 5-HT2A-Gq efficacy, but not β-arrestin2 efficacy, predicts psychedelic potential, and β-arrestin-biased agonists produce receptor downregulation and an anti-psychotic-like profile. |
Abstract
Summary 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.
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 8
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review. ACS Pharmacology & Translational Science June 14, 2024
- Psilocybin alters brain activity related to sensory and cognitive processing in a time-dependent manner medRxiv September 11, 2024
- The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents ACS Pharmacology & Translational Science May 29, 2025
- The Trouble With Psychedelic Cacti: Conflicting Meanings of San Pedro and Peyote Contemporary Drug Problems February 10, 2025
and 3 more in the library
Cites 35
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- 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