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

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 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-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'.

Keywords: Behavioral model; DMT; DOM; Head shake; Mescaline; N,N-dimethyltryptamine; NBOMe; Psilocybin; Psychedelic.

FIGURE 1.

Effect of 2,5-dimethoxy-4-methylamphetamine (DOM), 4-ethyl-2,5-dimethoxyamphetamine (DOET), 4-butyl-2,5-dimethoxyamphetamine (DOBU), and R-(-)-4-iodo-2,5-dimethoxyamphetamine (R-(-)-DOI) on the head twitch response (HTR). Data are presented as group means ± SEM for the entire 30-min test session. The individual data points for each compound are presented in Table S1. *p < 0.05, **p < 0.01, significant difference from the vehicle control group (Dunnett’s test).

FIGURE 2.

Hallucinogen potencies in humans and mice are robustly correlated (r = 0.9448). The numbers correspond to the agents in Table 3. Potencies in humans are plotted as log 1/total hallucinogenic dose (in moles); potencies in the mouse head-twitch response assay are plotted as log 1/ED₅₀ (in moles/kg).

FIGURE 3.

Hallucinogen potencies in mice and rats are robustly correlated. (TOP) Hallucinogen potencies in the mouse head-twitch response (HTR) assay are correlated (r = 0.9484) with published ED₅₀ values from rat drug discrimination studies using 0.08 mg/kg LSD as the training drug. (BOTTOM) Hallucinogen potencies in the mouse HTR assay are correlated (r = 0.9564) with published ED₅₀ values from rat drug discrimination studies using 1 mg/kg DOM as the training drug. The drug discrimination data are taken from Tables 4 and 5, respectively. Potencies in mice and rats are plotted as log 1/ED₅₀ (in moles/kg).