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.