Neuroscience letters
September 25, 2022
Alaina M Jaster, Jason Younkin, Travis Cuddy et al.
53 citations
The psychedelic compound DOI triggers more head-twitch behavior—a mouse proxy for human psychedelic effects—in female C57BL/6J mice than in males, a sex difference not seen in 129S6/SvEv mice. The 5-HT2A receptor antagonist volinanserin fully blocked this behavior in both sexes. Despite greater behavioral sensitivity in females, brain and plasma levels of DOI were lower in females 30 and 60 minutes after injection, and no sex difference appeared in frontal-cortex IP1 accumulation. These findings indicate strain-dependent and sex-related differences in the behavioral and pharmacokinetic responses to DOI, underscoring the need to include sex as a biological variable in preclinical psychedelic research.
Psychopharmacology
June 1, 2022
Alaina M Jaster, Harrison Elder, Samuel A Marsh et al.
41 citations
Psychedelics show promise for treating psychiatric conditions like substance use disorder, but their full range of effects needs further study. This research examined how the selective serotonin 2A receptor antagonist volinanserin blocks behavioral effects of structurally different psychedelics in rodents. Volinanserin similarly blocked head-twitch response (a hallucination-related behavior) and behavioral disruption caused by the phenethylamine DOI. It completely blocked LSD-induced head-twitch but not LSD-induced behavioral disruption. Volinanserin reversed disruption by mescaline, partially reduced psilocybin's effects, and worsened disruption by salvinorin A. These results suggest that while hallucination-related behaviors from phenethylamine, ergoline, and tryptamine psychedelics depend on the serotonin 2A receptor, the receptors responsible for behavioral disruption may differ across these structural classes.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
February 2, 2026
Maya C Gaines-Smith, Justin M Silverman, Michael Fiorillo et al.
3 citations
The drug MDMA, also known as ecstasy, is being studied as a possible aid in psychotherapy for hard-to-treat mental health conditions, but how it works in the brain is not fully understood. In experiments with mice, the S(+) form of MDMA, but not the R(-) form, activated a specific serotonin receptor (5-HT2AR) and caused changes in brain cell connections in the frontal cortex of males. The R(-) form had little effect except for a head-twitch response in females. Blocking the serotonin transporter with fluoxetine prevented these effects, showing that MDMA works indirectly by increasing serotonin levels. These results reveal that MDMA's effects on brain plasticity depend on both the drug's chemical form and the sex of the animal.
bioRxiv : the preprint server for biology
October 12, 2024
Mario de la Fuente Revenga, Javier González-Maeso
preprint
Psychedelics like LSD, psilocybin, and DOI produce their distinct effects by activating the serotonin 2A receptor (5-HT2AR). A new ex vivo method measures drug-induced activation of this receptor in mouse brain tissue by tracking changes in inositol monophosphate (IP1), a downstream signaling molecule. The method was specific to 5-HT2AR, as IP1 increases were absent in knockout mice. Head-twitch response counts, a behavioral correlate of psychedelic effects, correlated with IP1 levels in the frontal cortex. LSD increased IP1, while lisuride, a non-psychedelic 5-HT2AR agonist, did not. MDMA also raised IP1, likely by releasing serotonin, unlike 5-HTP or fluoxetine. This approach offers mechanistic insights into psychedelic and serotonergic drug action.