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

This 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).

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.”

Authors: Adam L. Halberstadt, Muhammad Chathaa, Adam K. Klein, Jason Wallach & Simon D. Brandt

Summary

LSD, DMT, DET and DPT are examples of hallucinogens. Animal models are used to study the effects of hallucinogens, and these models can be divided into two groups: those that test for behavior that is analogous to hallucinogen effects in humans, and those that test for behavior that does not.

Drug discrimination studies are used to compare the potency of hallucinogens, but can be limited in their relevance to typical hallucinogen use patterns in humans, and can also be affected by off-target pharmacological effects.

2.1. Animals

Male C57BL/6J mice were obtained from Jackson Laboratories and were housed in a climate-controlled room on a reverse-light cycle. They were provided with food and water and were used in experiments according to national institute of health guidelines.

2.3. Head-twitch response studies

HTR was assessed using a head-mounted magnet and a magnetometer detection coil. Head twitches were identified by trained personnel based on the following criteria: sinusoidal wavelets, at least three sequential head movements, and stable coil voltage immediately preceding and following each response.

  1. Results

A correlation analysis was performed to determine whether a relationship exists between the potency of hallucinogens in humans and their effects on head-twitch. The analysis confirmed that the potency of hallucinogens in humans is robustly and significantly correlated with the potency of hallucinogens in rats.

Hallucinogens exhibit varying degrees of receptor selectivity and those pharmacological differences can influence their interoceptive stimulus effects. The HTR induced by hallucinogens is solely mediated by 5-HT2A activation and is strongly correlated with drug discrimination ED50 values.

The results show that head-twitch and drug discrimination studies yield equivalent estimates of hallucinogen potency, and that the correlation between the two sets of data is just as strong as the correlation between the two sets of data.

  1. Discussion

This study evaluated the reliability and cross-species translation of the head-twitch response assay to assess hallucinogen potency in humans. The results showed that the head-twitch response assay can provide a quantitative assessment of hallucinogen potency that closely parallels results obtained in humans and in drug discrimination studies.

Researchers conducted HTR studies on 40 different hallucinogens, including DOET, DOBU, DON, DOC, -Et-2C-D, MDA, R-(-)-MDA, 25D-NBOMe, 25I-NBOH, and DET, and found that the HTR induced by these hallucinogens is nearly identical to the HTR induced by DOM in rats.

The correlation between human subjective potency and HTR is high, and this is probably due to the fact that most human potency data are based on the oral route of administration, and that interactions with the 5-HT1A receptor dampen the action of DMT at the 5-HT2A receptor.

There are significant differences in the response of mice to 5-HT2A receptor agonists, and the amount of head twitches induced by tryptamine in different mouse strains can be predicted by a linear regression model. However, more studies are needed to determine the predictive validity of this model.