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Cited by 351Psychedelics and Drug StudiesNeurotransmitter Receptor Influence on BehaviorReceptor Mechanisms and Signaling

Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens

Titeler, M., Lyon, R.A., Glennon, R.A.·1988·Psychopharmacology
DOI 10.1007/bf00176847
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Abstract

Alterations in brain serotonergic function have been implicated in the mechanism of action of LSD, mescaline, and other similarly acting hallucinogenic drugs of abuse such as STP (2,5-dimethoxyphenylisopropylamine; DOM). In order to test the hypothesis that the mechanism of action of LSD and phenylisopropylamine hallucinogens is through stimulation of a specific brain serotonin receptor sub-type, the affinities of these compounds for radiolabelled 5-HT2, 5-HT1A, 5-HT1B, and 5-HT1C receptors have been determined using recently developed in vitro radioligand binding methodologies. The 5-HT2 receptor was labelled with the agonist/hallucinogen radioligand 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine). The 5-HT1A, 5-HT1B, and 5-HT1C receptors were labelled with 3H-OH-DPAT, 3H-5-HT, and 3H-mesulergine, respectively. In general, the phenylisopropylamines displayed 10-100 fold higher affinities for the 5-HT2 receptor than for the 5-HT1C receptor and 100-1000 fold higher affinities for the 5-HT2 receptor than for the 5-HT1A or 5-HT1B receptor. There was a strong correlation between hallucinogenic potencies and 5-HT2 receptor affinities of the phenylisopropylamines (r = 0.90); the correlation coefficients for the 5-HT1A, 5-HT1B, and 5-HT1C were 0.73, 0.85, and 0.78, respectively. Because there is no evidence that 5-HT1A-selective or 5-HT1B-selective agonists are hallucinogenic and because the phenylisopropylamines are potent hallucinogens, a 5-HT2 receptor interaction is implicated and supports our previous suggestions to this effect. A secondary role for 5-HT1C receptors cannot be discounted at this time.(ABSTRACT TRUNCATED AT 250 WORDS)

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  • Under the same assay conditions as with LSD, the hallucinogenic compounds DOM, DOB and various other phenylpropylamines had nM affinity only at [3H]-ketanserin (mainly 5HT2A) binding sites in vitro.

    “Under the same assay conditions as with LSD above in [41], the hallucinogenic compounds DOM (11), 4-bromo-2,5-dimethoxyphenylisopropylamine (DOB, 12) and various other phenylpropylamines had nM affinity only at [3H]-ketanserin (mainly 5HT2A) binding sites in vitro.”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [41]

  • That series of compounds had 10-fold lower affinity at 5HT2C sites and 1000-fold lower affinity at 5HT1A and 5HT1B sites, indicating much greater selectivity than LSD.

    “That series of compounds had 10-fold lower affinity at 5HT2C sites and 1000-fold lower affinity at 5HT1A and 5HT1B sites, indicating much greater selectivity than LSD (1).”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [41]

  • Others reported Ki values for LSD of 0.54 nM at 5HT2A/C sites labelled with [3H]ketanserin, 0.43 nM at 5HT1A sites, and 6.6 nM at 5HT1B sites, confirming the considerable 5HT1-binding propensity of LSD.

    “Others reported Ki values for LSD (1) of 0.54 nM at 5HT2A/C sites labelled with [3H]ketanserin, 0.43 nM at 5HT1A sites, and 6.6 nM at 5HT1B sites [41], thus confirming the considerable 5HT1-binding propensity of LSD (1).”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [41]

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Authors
Titeler, M., Lyon, R. A., & Glennon, R. A.
Affiliations
  • Albany Medical College (US)
  • Virginia Commonwealth University (US)
ORCID
Glennon, R.A.
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
1988-02
Volume
94
Issue
2
Pages
213-6
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/bf00176847
OpenAlex
W2087542866
Cited by
343
References
20
Citations by year
2025: 10 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 4 · 2020: 11 · 2019: 3 · 2018: 6 · 2017: 11 · 2016: 5 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 5
FWCI
25.17
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (MH40716-01A2)
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-HT2 receptor, LSD, phenylisopropylamines, hallucinogens, serotonin receptors, 5-HT1A receptor, 5-HT1B receptor, 5-HT2C receptor, receptor binding affinity, mechanism of action, mescaline, DOM
MeSH terms
Amphetamines, Animals, Behavior, Animal, Brain, DOM 2,5-Dimethoxy-4-Methylamphetamine, Hallucinogens, Lysergic Acid Diethylamide, Male, Radioligand Assay, Rats, Inbred Strains, Receptors, Serotonin, Rats, In Vitro Techniques

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