Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice

Rika Takaba, Daisuke Ibi, Keisuke Yoshida, Eri Hosomi, Ririna Kawase, Hiroko Kitagawa, Hirotaka Goto, Mizuki Achiwa, Kento Mizutani, Kyosuke Maeda, Javier González-Maeso, Shinji Kitagaki, Masayuki Hiramatsu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h post-treatment. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than anxiolytic effects.

Original languageEnglish
Pages (from-to)3019-3035
Number of pages17
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number5
StatePublished - May 2024
Externally publishedYes


  • DOI
  • Major depressive disorder
  • Psilocin (psilocybin)
  • Serotonergic psychedelics
  • TCB-2


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