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

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A Correction to this article was published on 12 February 2024

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Abstract

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.

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Data availability

The datasets created during this investigation are available upon request from the corresponding author.

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Acknowledgements

The authors would like to thank the Division for Research of Laboratory Animals, Meijo University, for technical assistance. We would also like to thank Takayoshi Mamiya, Ph.D. (Meijo University), for technical advice regarding the behavioral assay.

Funding

This research was supported by the Uehara Memorial Foundation, SENSHIN Medical Research Foundation, TOYOAKI Scholarship Foundation, YOKOYAMA Foundation for Clinical Pharmacology (YRY-1909), Pharmacological Research Foundation, Tokyo, Research Foundation for Pharmaceutical Sciences, Smoking Research Foundation, Takeda Science Foundation, Brain Science Foundation, NOVARTIS Foundation (Japan) for the Promotion of Science (D.I.), and Research Center for Pathogenesis of Intractable Disease from the Research Institute of Meijo University (D.I. and M.H.), and NIH grant R01MH084894 (J.G.M.). Japan Society for the Promotion of Science 15H06719, 16K19786, 19K07332, and 22K06872 (D.I.) were used in this study. This work was partially supported by a Nagai Memorial Research Scholarship (no. N-223903) obtained from the Pharmaceutical Society of Japan (R.T.). The Matching Fund Subsidy for Private Universities and the Private University Research Branding Project of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT) purchased the confocal laser scanning fluorescence microscope used in this study.

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Author notes

  1. Rika Takaba and Daisuke Ibi contributed equally to this work.

Authors and Affiliations

  1. Department of Chemical Pharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan, 468-8502

    Rika Takaba, Daisuke Ibi & Masayuki Hiramatsu

  2. Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan, 468-8502

    Daisuke Ibi, Eri Hosomi, Ririna Kawase, Hiroko Kitagawa, Hirotaka Goto, Mizuki Achiwa, Kento Mizutani, Kyosuke Maeda & Masayuki Hiramatsu

  3. Department of Medical Chemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan, 468-8502

    Keisuke Yoshida & Shinji Kitagaki

  4. Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Javier González-Maeso

Authors
  1. Rika Takaba
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  2. Daisuke Ibi
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  3. Keisuke Yoshida
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  4. Eri Hosomi
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  5. Ririna Kawase
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  6. Hiroko Kitagawa
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  7. Hirotaka Goto
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  8. Mizuki Achiwa
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  9. Kento Mizutani
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  10. Kyosuke Maeda
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  11. Javier González-Maeso
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  12. Shinji Kitagaki
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  13. Masayuki Hiramatsu
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Contributions

Rika Takaba: Investigation, data curation, writing, and editing.

Eri Hosomi, Ririna Kawase, Hiroko Kitagawa, Hirotaka Goto, Mizuki Achiwa, Kento Mizutani, and Kyosuke Maeda: Investigation and data curation.

Keisuke Yoshida, Shinji Kitagaki: Synthesis of psilocin.

Javier González-Maeso: Accurate technical and academic advice.

Masayuki Hiramatsu: Writing and editing, and project administration.

Daisuke Ibi: Conceptualization, methodology, writing and editing, project administration, and funding acquisition.

The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Rika Takaba, Daisuke Ibi or Masayuki Hiramatsu.

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Ethics approval

All experiments followed the guidelines established by the Japanese Pharmacological Society and Institute for Experimental Animals at Meijo University. Protocols were approved by the Animal Ethics Board of Meijo University [permit no. (2017–2023)-11].

Competing interests

The authors declare no competing interests.

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The original version of this article was revised. The name of the 10th author is now corrected.

Supplementary Information

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Supplemental Fig. 1

Role of 5-HT2C in the antidepressant-like effect of serotonergic psychedelics in mice. Experimental schedule (a). FST was carried out 24 h after administration of psilocin at 1.5 mg/kg or DOI at 0.1 mg/kg in mice, in which the immobility time was measured for 15 min (b, c). SB242084, a 5-HT2C antagonist, was injected 30 min before the administration of psilocin or DOI. Doses of SB242084 are shown below the vertical line in each graph. Values represent the median with interquartile range (n = 6–17). Significance levels: *p < 0.05, **p < 0.01, vs. vehicle (Kruskal–Wallis nonparametric one-way ANOVA followed by Bonferroni’s test). n.s.: not significant. (DOCX 125 KB)

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Takaba, R., Ibi, D., Yoshida, K. et al. Ethopharmacological evaluation of antidepressant-like effect of serotonergic psychedelics in C57BL/6J male mice. Naunyn-Schmiedeberg's Arch Pharmacol 397, 3019–3035 (2024). https://doi.org/10.1007/s00210-023-02778-x

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