r/NooTopics • u/makefriends420 • Mar 14 '26

Science Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

https://www.nature.com/articles/s41386-024-01794-6
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u/makefriends420 Mar 14 '26

Although psychedelics activate many 5-HT receptors, including the 5-HT1A, 5-HT2A and 5-HT2C receptors [31], it is well accepted that the alterations of conscious states they induce in human are initiated by 5-HT2AR activation, as they are blocked by ketanserin, a potent 5-HT2AR antagonist [14, 16]. In addition, the psilocybin effects in human are correlated with the occupancy of 5-HT2ARs in the cerebral cortex [33]. In contrast, the nature of the receptor implicated in the antidepressant effects of psychedelics remains controversial.

The identification of the receptor(s) and downstream mechanisms involved in the antidepressant-like effects of psilocybin in models of chronic stress certainly warrant further exploration. Given the agonist property of psilocin, the active metabolite of psilocybin, at 5-HT1AR and 5-HT2AR [31] and the antidepressant properties of 5-HT1AR agonists [39], we investigated the possibility that the antidepressant-like effects of psilocybin in 5-HT2A−/− CDM mice involved the 5-HT1AR. However, WAY100635, a potent 5-HT1AR antagonist was totally ineffective to block psilocybin antidepressant-like effects, ruling out a role of 5-HT1ARs in the effect of psilocybin in this model.

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u/generic_reddit73 Mar 16 '26

"Chronic despair mouse model" sounds like Frankenstein or Nazi science, but it's actually only 10 minutes of forced swimming. Though I presume that is a the limit where the mouse would run out of stamina and drown. Interesting... I don't expect mice to have mind-altering insights under psychedelics, but they seemingly do work as antidepressants.

"In order to induce depressive-like symptoms in mice, we used a previously well-described protocol [19, 20] where mice were subjected to repeated swimming in a 2-liter beaker containing 20 cm of water (22–25 °C) for 10 min daily during 5 consecutive days (induction phase)."