Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex
Open accessAbstract
Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit.In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.
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Findings from in vivo studies investigating acute effects of a single dose of 5-MeO-DMT, DMT, psilocybin, and LSD (37%) suggest altered cellular plasticity of structural and functional nature.
“Findings from in vivo studies investigating acute effects of a single dose of 5-MeO-DMT, DMT, psilocybin, and LSD (37%) suggest altered cellular plasticity of structural and functional nature (54–60).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [56]
The Results (page not available in our copy) report altered cortical gene expression one hour after a single LSD injection in mice, supporting an acute cellular response. The paper does not show structural plasticity, and it did not test 5-MeO-DMT, DMT, or psilocybin; the 37% figure is not established by this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA single dose of LSD (0.20, 0.24, 0.5, 1.0 mg/kg i.p.) stimulated the mRNA expression of plasticity-promoting genes in the cortex of rats and mice, within 1-2 h after administration and in a time- and dose-dependent manner.
“A single dose of LSD (0.20, 0.24, 0.5, 1.0 mg/kg i.p.) stimulated the mRNA expression of plasticity-promoting genes in the cortex of rats and mice, within 1–2 h after administration and in a time- and dose-dependent manner (56–59).”
From Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. (2021) · cites this paper as [56]
The Results (page not available in our copy) report that LSD altered cortical transcripts in mice one hour after injection, including activation of egr-1, egr-2, and period-1; Figure 2 identifies an LSD dose of 0.24 mg/kg i.p. The paper does not establish this gene-expression finding in rats or at the other listed LSD doses. Its time-course and dose-response gene-expression experiments used DOI, not LSD. (LLM, conf=0.90)
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References 55 · Cited by 297
- Authors
- González-Maeso, J., Yuen, T., Ebersole, B. J., Wurmbach, E., Lira, A., Zhou, M., Weisstaub, N., Hen, R., Gingrich, J. A., & Sealfon, S. C.
- Affiliations
- Columbia University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-10-01
- Volume
- 23
- Issue
- 26
- Pages
- 8836-8843
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740401
- OpenAlex
- W2171104921
- Semantic Scholar
- 08602db4bfc94872253386e2aa279bd251e48e03
- Cited by
- 297
- References
- 55
- Citations by year
- 2026: 5 · 2025: 18 · 2024: 23 · 2023: 20 · 2022: 19 · 2021: 24 · 2020: 15 · 2019: 10 · 2018: 19 · 2017: 12 · 2016: 14 · 2015: 6 · 2014: 10 · 2013: 10 · 2012: 17
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eusko Jaurlaritza
- National Institutes of Health
- National Institute on Drug Abuse (P01DA012923)
- 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
- 5-HT2A receptor, hallucinogens, somatosensory cortex, 2,5-dimethoxy-4-iodoamphetamine, lysergic acid diethylamide, head-twitch response, G protein-coupled receptor signaling
- MeSH terms
- Animals, Behavior, Animal, Cell Line, Feasibility Studies, Hallucinogens, Humans, Kidney, Mice, Mutant Strains, Receptors, Serotonin, Somatosensory Cortex, Transcription, Genetic, Signal Transduction, Gene Expression, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Receptor, Serotonin, 5-HT2A, Mice
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