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

Serotonergic psychedelics like psilocin, DOI, and TCB-2 produce antidepressant-like effects in mice by activating the serotonin 5-HT2A receptor. Mice given a single injection of these drugs showed less immobility in the forced swimming and tail-suspension tests 24 hours later, effects blocked by a 5-HT2A antagonist. The antidepressant-like effect of psilocin lasted at least three weeks. However, only psilocin reduced anxiety-like behavior in the novelty-suppressed feeding test, and this effect was not blocked by the 5-HT2A antagonist. The drugs did not alter spontaneous movement or head-twitch responses. The findings indicate 5-HT2A mediates antidepressant but not anxiolytic effects of these psychedelics.

Study at a glance

Abstract

Abstract Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT 2A 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. 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 24 h post-treatment. 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 an anxiolytic effects.