Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors
Abstract
Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT. Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT.
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DMT substituted for a 5HT2A agonist in a rat behavioral drug discrimination trial against the antagonist ketanserin.
“Prima facia, this seems unlikely since DMT (9) substituted for a 5HT2A agonist in a rat behavioral drug discrimination trial against the antagonist ketanserin (7) [50].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [50]
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“Prima facia, this seems unlikely since DMT (9) substituted for a 5HT2A agonist in a rat behavioral drug discrimination trial against the antagonist ketanserin (7) [50].”
Background
- Authors
- Smith, R.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Smith, R
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 1998-11
- Volume
- 61
- Issue
- 3
- Pages
- 323-330
- ISSN
- 0091-3057 (ISSN-L)
- OpenAlex
- W1510556999
- Cited by
- 147
- References
- 1
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 9 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 10 · 2014: 6 · 2013: 7 · 2012: 5
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH34007)
- National Institute on Drug Abuse (DA-05181, R01DA005181)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- N,N-dimethyltryptamine, 5-HT2A receptor, serotonin 5-HT2C receptor, hallucinogens, receptor agonism, partial agonism, receptor desensitization, phosphoinositide hydrolysis, ketanserin, digital object identifiers, choroid plexus, tryptamine analogs
- MeSH terms
- Animals, Cell Line, Choroid Plexus, N,N-Dimethyltryptamine, Discrimination, Psychological, Hallucinogens, Male, Psychomotor Performance, Receptors, Serotonin, Time Factors, 3T3 Cells, Rats, Sprague-Dawley, Serotonin Receptor Agonists, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Mice, Rats
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