Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test

BACKGROUND: Major depressive disorder is one of the most debilitating psychiatric disorders worldwide. First-line treatments such as selective serotonin reuptake inhibitors have significant limitations, including delayed onset of therapeutic effects and treatment resistance in about 30% of patients. Increasing evidence suggests that acute administration of serotonergic psychedelics, such as psilocybin, produces rapid and long-lasting antidepressant effects, including in treatment-resistant patients. However, it remains unknown which specific 5-HT receptor subtype mediates psilocybin's antidepressant activity. METHODS: We examined in Wistar rats whether pretreatment with the 5-HT2B receptor (5-HT2BR) antagonist RS-127445 (0.32, 1.0, or 3.2 mg/kg) blocked the rapid (day 1) and sustained (day 21) behavioral effects of a single psilocybin administration (0.32 mg/kg) in the forced swim test (FST), a test with predictive validity for antidepressant efficacy. We also measured the impact of RS-127445 on psilocybin-induced head-twitch response (HTR), a behavioral proxy in rodents for psychedelic properties. RESULTS: Our data showed that psilocybin produced both a rapid and sustained decrease in immobility and an increase in climbing behavior in the FST and significantly increased HTR counts. Although RS-127445 did not affect HTR counts at any tested dose, it dose-dependently reversed both the rapid and sustained psilocybin-induced reductions in immobility and increases in climbing behavior. CONCLUSION: These findings indicate that 5-HT2BRs are required for psilocybin's behavioral effects in the FST, but are not required for its HTR. The results add to evidence that psilocybin's predictive validity in the FST can be dissociated from its 5-HT2A-mediated psychedelic effects.