Neuropharmacology
May 1, 2020
Adam L Halberstadt, Muhammad Chatha, Adam K Klein et al.
274 citations
Serotonergic hallucinogens like LSD cause head twitches in rodents through 5-HT2A receptor activation. This study tested whether the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm correlates with their potencies in rats and humans. Dose-response experiments with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice expanded HTR potency data to 41 compounds. For 36 agents with human data, a strong positive correlation (r = 0.9448) was found between mouse HTR potencies and human hallucinogenic potencies. HTR potencies also correlated with drug discrimination ED50 values in rats trained with LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). These three behavioral effects show consistent potencies linked to 5-HT2A receptor activation, supporting the HTR assay as a predictive preclinical model for hallucinogen potency in humans.
ACS chemical neuroscience
May 6, 2020
Emil Marcher-Rørsted, Adam L Halberstadt, Adam K Klein et al.
20 citations
The 2,5-dimethoxy motif found in many phenethylamine psychedelics has been considered essential for activating the serotonin 2A receptor (5-HT2AR). This study synthesized derivatives of 2C-B and DOB lacking either the 2- or 5-methoxy group and tested them in binding and functional assays at 5-HT2AR and 5-HT2CR, as well as in mice for head-twitch response, a behavioral proxy for psychedelic activity. Removing either methoxy group caused a modest drop in binding affinity and functional potency at both receptors, with larger effects from removing the 2-methoxy group. However, in mice, removal of either group drastically reduced head-twitch response. Thus, the 2,5-dimethoxy motif is important for in vivo potency, but this does not correlate with in vitro receptor affinity or potency.
Neuropharmacology
May 1, 2025
Michael Noback, Johnny A Kenton, Adam K Klein et al.
2 citations
A compound called 2,5-dimethoxy-4-propylamphetamine (DOPR), a psychedelic that activates 5-HT2A receptors, can increase motivation in mice with low baseline motivation without causing hallucinogenic-like effects. In a progressive ratio breakpoint task (PRBT) involving 80 mice, doses as low as 0.0106 mg/kg improved performance only in animals with low initial motivation; high-performing mice were unaffected. The head-twitch response (HTR) assay in 72 mice showed hallucinogenic-like effects only at doses of 0.1 mg/kg or higher. These results suggest that low doses of DOPR might treat amotivated states while avoiding hallucinogenic side effects, warranting further research in rodents with disease-relevant conditions.