BEHAVIORAL ANALYSES OF ANTIDEPRESSANT-LIKE EFFECT OF SEROTONERGIC PSYCHEDELICS IN MICE

Abstract Background Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through the serotonin 5-HT2A receptor (5-HT2A). Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. Aims & Objectives The involvement of 5-HT2A in mediating the therapeutic effects of serotonergic psychedelics remains unclear. In this study, we 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 after treatment. Method Male C57BL/6J mice (7–9 weeks old) were utilized in this study. The forced-swimming test (FST) and tail-suspension test (TST) were performed to investigate the antidepressant-like effect of psychedelics in mice. The anxiolytic-like effect of psychedelics was assessed using the novelty-suppressed feeding test (NSFT). Mice subjected to either chronic unpredictable mild stress (CUMS) or chronic corticosterone (CORT) treatment were employed as animal models of depression. All drugs were administered intraperitoneally. Results Mice with acute psychedelic treatment exhibited significantly shorter immobility times in the FST and 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 NSFT, the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not antagonize 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. Lastly, we observed that mice subjected to either CUMS or CORT treatment exhibited a decrease in immobility time in the FST, which was reversed by a single dose of DOI. Discussion & Conclusion These results suggest that 5-HT2A plays a central role in the antidepressant effects of serotonergic psychedelics, which may contribute to the therapeutic effects of psychedelics in animal models of depression.