Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species
This mouse study investigates the correlation between the hallucinogens potency in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species such as rats and humans. It used dose-response studies with psychedelics in mice and found a very strong correlation (r=0.95) with earlier human data (n=36).
Authors
- Adam Halberstadt
- Simon Brandt
Published
Abstract
Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A 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 ED50 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-HT2A 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-HT2A agonists in humans.
Research Summary of 'Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species'
Introduction
Halberstadt and colleagues outline the pharmacological diversity of classical serotonergic hallucinogens, noting major structural families (ergolines, phenylalkylamines, tryptamines) and differences in receptor selectivity. Earlier research established that 5-HT2A receptor agonism is central to hallucinogen effects in humans and that animal models have been useful for probing neurochemical mechanisms. However, the behavioural complexity of human psychedelic effects has made it challenging to develop animal assays with both construct and predictive validity for potency. Against this background, the investigators evaluated whether the mouse head-twitch response (HTR) — a rapid, high-frequency head rotation elicited by 5-HT2A activation — can provide a quantitative measure of hallucinogen potency that translates across species. Specifically, they aimed to test whether ED50 values derived from the mouse HTR correlate with reported behavioural and subjective potency measures in rats (drug-discrimination studies) and in humans, thereby assessing the HTR assay's utility for structure–activity relationship (SAR) studies and cross-species prediction of hallucinogenic potency.
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Study Details
- Study Typeindividual
- Journal
- Compounds
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- APA Citation
Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach, J., & Brandt, S. D. (2020). Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology, 167, 107933. https://doi.org/10.1016/j.neuropharm.2019.107933
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