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
Naunyn-Schmiedeberg's archives of pharmacology May 1, 2024 Peer reviewed DOI: 10.1007/s00210-023-02778-x via PubMed
Summary
Psychedelic compounds like psilocybin show remarkable promise in treating major depressive disorder, with effects lasting weeks after a single dose. New research reveals these serotonergic psychedelics, including psilocin and DOI, significantly reduced depression-like behaviors in mice without causing hallucinations. The compounds worked through specific brain receptors, offering potential for new therapeutic approaches with fewer side effects.
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.