Serotonergic psychedelics like psilocin (the active metabolite of psilocybin), DOI, and TCB-2 produce antidepressant-like effects in mice by activating the 5-HT2A receptor. Twenty-four hours after a single injection, treated mice showed significantly less immobility in the forced swimming test and tail-suspension test—indicating reduced behavioral despair—compared to control mice. Blocking the 5-HT2A receptor with volinanserin eliminated these antidepressant-like effects. Psilocin's effect in the forced swimming test lasted at least three weeks. In the novelty-suppressed feeding test, psilocin reduced feeding latency (an anxiolytic-like effect), but volinanserin did not block this, and DOI and TCB-2 had no effect. None of the drugs altered spontaneous movement or head-twitch response. The findings suggest 5-HT2A activation mediates antidepressant but not anxiolytic effects of these psychedelics.
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.