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Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

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Halberstadt, Adam L., Chatha, Muhammad, Klein, Adam K., Wallach, Jason, Brandt, Simon D.·2020·Neuropharmacology
DOI 10.1016/j.neuropharm.2019.107933PMC PMC9191653
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Abstract

Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT 2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED 50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT 2A receptor activation. We present evidence that hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of hallucinogen psychopharmacology and in structure-activity relationship studies of hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the hallucinogenic potency of 5-HT 2A agonists in humans. "This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

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  • Head-twitch response is a behavioral proxy for hallucinations in mice that correlates exceptionally well with hallucinogenic potency in humans.

    “a behavioral proxy for hallucinations in mice that correlates exceptionally well with hallucinogenic potency in humans”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [253]

  • The mouse head-twitch response behavioral paradigm and rat trials of drug discrimination may serve better to predict hallucinogenic potency of drugs in humans.

    “However, the mouse head-twitch response behavioral paradigm and rat trials of drug discrimination may serve better to predict hallucinogenic potency of drugs in humans [28].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [28]

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Cited by

Sorted by citations

Authors
Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach, J., & Brandt, S. D.
Affiliations
  • University of California San Diego (US)
  • University of the Sciences (US)
  • Liverpool John Moores University (GB)
Corresponding author
Halberstadt, Adam L.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2020-05
Volume
167
Pages
107933
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2019.107933
PMC
PMC9191653
OpenAlex
W2999364864
Cited by
278
References
12
Citations by year
2026: 45 · 2025: 65 · 2024: 47 · 2023: 44 · 2022: 38 · 2021: 20 · 2020: 18 · 2019: 1
FWCI
12.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute on Drug Abuse
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Keywords
hallucinogens, head-twitch response, 5-HT2A receptor, lysergic acid diethylamide, drug discrimination, predictive validity, translational validity, structure-activity relationship, serotonin receptor agonists
MeSH terms
Animals, Discrimination Learning, Dose-Response Relationship, Drug, Hallucinogens, Humans, Male, Mice, Inbred C57BL, Species Specificity, Head Movements, Receptor, Serotonin, 5-HT2A, Mice, Rats, Serotonin 5-HT2 Receptor Agonists, Magnetometry

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