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Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice
Open accessAbstract
Psilocin (4-hydroxy- N, N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT 2C receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT 2A receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT 1A antagonist WAY-100635 but were not altered by the selective 5-HT 2C antagonist SB 242,084 or by 5-HT 2A receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT 2C and 5-HT 1A receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6–9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT 2A sites but is inactive at the 5-HT 1A receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin represents a potentially useful alternative to psilocybin for development as a potential therapeutic agent.
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“Psilocybin, a classical psychedelic, can play its antidepressant roles by activating 5-HT 2A receptors (5-HT 2A R). 385”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [385]
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Cites
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“In recent years, a number of studies have examined the effects of psilocybin in human volunteers (Carter et al., 2004, 2005b; Gouzoulis-Mayfrank et al., 1998, 1999; Griffiths et al., 2006; Umbricht et al., 2003; Vollenweider et al., 1997, 2007; Wittmann et al., 2007).”
Nichols, D. E. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2003.11.002 · Cited by 1,211
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Self-citationPsilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action
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Sorted by citations
Nichols, D. E. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011478 · Cited by 1,762
Major depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,244
“385 Thus, to block the 5-HT 2A R can not produce the antidepressant effects of psilocybin, only induce the hallucinogenic-like behaviors in mice.”
BackgroundPsilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
Shao, L.-X., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021) · Neuron · doi:10.1016/j.neuron.2021.06.008 · Cited by 626
Johnson, M. W., Hendricks, P. S., Barrett, F. S., & Griffiths, R. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.010 · Cited by 506
Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens
Halberstadt, A. L., & Geyer, M. A. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.017 · Cited by 435
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Metadata
- Authors
- Halberstadt, A. L., Koedood, L., Powell, S. B., & Geyer, M. A.
- Affiliations
- Department of Psychiatry, University of California, La Jolla, CA, USA.
- Corresponding author
- Geyer, Mark A
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2010-12-08
- Volume
- 25
- Issue
- 11
- Pages
- 1548-1561
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- PMC
- PMC3531560
- OpenAlex
- W2107441654
- Cited by
- 213
- References
- 65
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 31 · 2023: 20 · 2022: 18 · 2021: 8 · 2020: 11 · 2019: 9 · 2018: 13 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 4
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of California, San Diego
- National Institute of Mental Health
- National Institute on Drug Abuse (F32DA025412, R01DA002925)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Hallucinations in medical conditions
- Keywords
- psilocin, psilocybin, 5-MeO-DMT, serotonin receptors, 5-HT1A receptor, 5-HT2A receptor, 5-HT2C receptor, head-twitch response, locomotor activity, WAY-100635, SB242084, receptor selectivity, hallucinogens
- MeSH terms
- Animals, Behavior, Hallucinogens, Male, Methoxydimethyltryptamines, Mice, Inbred C57BL, Motor Activity, Piperazines, Psilocybin, Pyridines, Receptors, Serotonin, Serotonin Antagonists, Mice, Knockout, Mice
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