Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice.
Grant C. Glatfelter, Allison A Clark, Natalie G. Cavalco, Antonio Landavazo, John S. Partilla, Marilyn Naeem, James A. Golen, Andrew R Chadeayne, David R. Manke, Bruce E. Blough, John D. Mccorvy, Michael H. Baumann
ACS Chemical Neuroscience December 18, 2024 DOI: 10.1021/acschemneuro.4c00513 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | C57Bl/6J mice |
| Interventions | N-allyl and 2-methyl analogs |
| Topics | 5-MeO-DMT DMT Serotonin |
| Keywords | Brain chemistry 5-ht1a 5-ht2a Head twitch response Mice Tryptamines Psychedelics Serotonin receptors Pharmacology |
| Citations | 14 |
| Key findings | 5-HT1A receptor agonism dampens 5-HT2A-mediated head twitch responses in mice, and blocking 5-HT1A can unmask latent psychedelic-like activity in certain 5-MeO-DMT analogs. |
Abstract
5-methoxy-N,N-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its N-alkyl, N-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT2A) and 1A receptors (5-HT1A), and 3) to examine the influence of 5-HT1A on 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT2A and 5-HT1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED50 range = 0.2-1.8 mg/kg) and maximal effects (Emax range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED50 range = 3.2-20.6 mg/kg). 5-HT2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT1A antagonist pretreatment enhanced HTRs. In general, N,N-dialkyl and N-isopropyl derivatives displayed HTR activity, while the N-methyl, N-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT1A unmasked latent HTR activity for the N-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT1A agonist activity can dampen 5-HT2A-mediated HTRs. Suppression of 5-HT2A-mediated HTRs by 5-HT1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT1A agonism in modulating acute psychoactive effects of 5-HT2A agonists.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cited by 13
- Psychedelic-like effects induced by 2,5-dimethoxy-4-iodoamphetamine, lysergic acid diethylamide, and psilocybin in male and female C57BL/6J mice. Psychopharmacology May 17, 2025
- The ABCs of psychedelics: a preclinical roadmap for drug discovery. TIPS - Trends in Pharmacological Sciences August 28, 2025
- Biased Signaling in Psychedelic Action. The Annual Review of Pharmacology and Toxicology August 12, 2025
- Pathway-selective signaling of serotonergic psychedelics at 5-HT receptors: Implications for psychoactivity, safety, and therapeutic potential European Neuropsychopharmacology April 10, 2026
- The 4-alkyl chain length of 2,5-dimethoxyamphetamines differentially affects in vitro serotonin receptor actions versus in vivo psychedelic-like effects Molecular Psychiatry November 5, 2025
and 8 more in the library
Cites 81
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- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. Journal of Psychopharmacology February 2, 2022
- Psychedelics and the Human Receptorome PLoS One 2010
and 76 more in the library