Differences across sexes on head-twitch behavior and 5-HT2A receptor signaling in C57BL/6J mice.
Alaina M Jaster, Jason Younkin, Travis Cuddy, Mario de la Fuente Revenga, Justin L Poklis, Mikhail G Dozmorov, Javier González-Maeso
Neuroscience letters September 25, 2022 Peer reviewed DOI: 10.1016/j.neulet.2022.136836 via PubMed
Summary
DOI, a psychedelic compound, caused more head-twitch behavior in female C57BL/6J mice than in males, indicating sex-specific effects. However, the accumulation of inositol monophosphate in the frontal cortex did not show sex differences. Additionally, female mice had lower brain and plasma concentrations of DOI compared to males 30 and 60 minutes after administration. These findings highlight the importance of considering sex as a biological variable in preclinical studies of psychedelics.
Study at a glance
| Population | C57BL/6J and 129S6/SvEv mice |
|---|---|
| Key finding | DOI elicited more head-twitch behavior in female compared to male C57BL/6J mice. |
Abstract
Psychedelics, also known as classical hallucinogens, affect processes related to perception, cognition and sensory processing mostly via the serotonin 5-HT2A receptor (5-HT2AR). This class of psychoactive substances, which includes lysergic acid diethylamide (LSD), psilocybin, mescaline and the substituted amphetamine 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), is receiving renewed attention for their potential therapeutic properties as it relates to psychiatric conditions such as depression and substance use disorders. Current studies focused on the potentially clinical effects of psychedelics on human subjects tend to exclude sex as a biological variable. Much of the understanding of psychedelic pharmacology is derived from rodent models, but most of this preclinical research has only focused on male mice. Here we tested the effects of DOI on head-twitch behavior (HTR) - a mouse behavioral proxy of human psychedelic potential - in male and female mice. DOI elicited more HTR in female as compared to male C57BL/6J mice, a sex-specific exacerbated behavior that was not observed in 129S6/SvEv animals. Volinanserin (or M100907) - a 5-HT2AR antagonist - fully prevented DOI-induced HTR in male and female C57BL/6J mice. Accumulation of inositol monophosphate (IP1) in the frontal cortex upon DOI administration showed no sex-related effect in C57BL/6J mice. However, the pharmacokinetic properties of DOI differed among sexes - brain and plasma concentrations of DOI were lower 30 and 60 min after drug administration in female as compared to male C57BL/6J mice. Together, these results suggest strain-dependent and sex-related differences in the behavioral and pharmacokinetic profiles of the 5-HT2AR agonist DOI in C57BL/6J mice, and support the importance of studying sex as a biological variable in preclinical psychedelic research.