Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice

Featured Paper of the Month – September 2025

Published in ACS Chemica Neuroscience by Grant Glatfelter and Michael Baumann of the NIDA IRP Designer Drug Research Unit.

Summary

A variety of psychedelic compounds are being evaluated for therapeutic potential, but acute psychoactive effects can be problematic. The psychedelic effects of tryptamines, like 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), involve activation of 5-HT2A receptors in the brain. Here, we show that 5-MeO-DMT and related analogs potently activate 5-HT1A receptors, which tend to decrease the magnitude of 5-HT2A-mediated behavioral effects in mice. Our findings suggest the balance between 5-HT1A and 5-HT2A agonist effects could be optimized to engender less intense psychedelic experiences, thereby affording safer and more tolerable 5-HT2A medications.

Publication Information

Glatfelter, Grant C; Clark, Allison A; Cavalco, Natalie G; Landavazo, Antonio; Partilla, John S; Naeem, Marilyn; Golen, James A; Chadeayne, Andrew R; Manke, David R; Blough, Bruce E; McCorvy, John D; Baumann, Michael H

Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice Journal Article

In: ACS Chem Neurosci, vol. 15, no. 24, pp. 4458–4477, 2024, ISSN: 1948-7193.

Abstract | Links

@article{pmid39636099b,

title = {Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice},

author = {Grant C Glatfelter and Allison A Clark and Natalie G Cavalco and Antonio Landavazo and John S Partilla and Marilyn Naeem and James A Golen and Andrew R Chadeayne and David R Manke and Bruce E Blough and John D McCorvy and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/39636099/},

doi = {10.1021/acschemneuro.4c00513},

issn = {1948-7193},

year  = {2024},

date = {2024-12-01},

urldate = {2024-12-01},

journal = {ACS Chem Neurosci},

volume = {15},

number = {24},

pages = {4458--4477},

abstract = {5-methoxy-,-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 -alkyl, -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-HT) and 1A receptors (5-HT), and 3) to examine the influence of 5-HT on 5-HT-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-HT and 5-HT. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED range = 0.2-1.8 mg/kg) and maximal effects ( range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED range = 3.2-20.6 mg/kg). 5-HT antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT antagonist pretreatment enhanced HTRs. In general, ,-dialkyl and -isopropyl derivatives displayed HTR activity, while the -methyl, -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT unmasked latent HTR activity for the -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT agonist activity can dampen 5-HT-mediated HTRs. Suppression of 5-HT-mediated HTRs by 5-HT 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-HT agonism in modulating acute psychoactive effects of 5-HT agonists.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

5-methoxy-,-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 -alkyl, -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-HT) and 1A receptors (5-HT), and 3) to examine the influence of 5-HT on 5-HT-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-HT and 5-HT. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED range = 0.2-1.8 mg/kg) and maximal effects ( range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED range = 3.2-20.6 mg/kg). 5-HT antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT antagonist pretreatment enhanced HTRs. In general, ,-dialkyl and -isopropyl derivatives displayed HTR activity, while the -methyl, -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT unmasked latent HTR activity for the -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT agonist activity can dampen 5-HT-mediated HTRs. Suppression of 5-HT-mediated HTRs by 5-HT 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-HT agonism in modulating acute psychoactive effects of 5-HT agonists.