Psilocybin, a tryptamine alkaloid found naturally in numerous Psilocybe mushroom species, is currently being investigated for its therapeutic potential in treating several neurobehavioral and psychiatric diseases. Our previous data showed that the 5-HT2B receptor (5-HT2BR) immobility and increases in climbing behavior in the forced swim test (FST), revealing that psilocybin's predictive validity in the FST can be dissociated from its 5-HT2A-mediated psychedelic effects. Assessing how psilocybin modulates other innate, ethologically relevant behaviors beyond the FST is critical to fully mapping its 5-HT2BR-dependent profile. Given the emerging relevance of self-grooming in modeling various affective brain disorders, studying its microstructure offers important insights into the complex neural regulation of behavioral sequences. Specifically, this study aimed to characterize the effect of psilocybin on novelty-induced grooming in Wistar rats using the Grooming Analysis Algorithm (GAA) and evaluated whether RS-127445 reversed these behavioral changes. Our data showed that psilocybin reduced grooming as quantified by traditional grooming measures (total grooming time and number of bouts), and that this reduction resulted from a selective suppression of abnormal, non-comfort behavioral grooming microstructure. RS-127445 reversed the psilocybin-induced reduction in traditional measures and blocked psilocybin's selective suppression of fragmented bout and aberrant transition patterns. These results extend our understanding of psilocybin's behavioral profile, demonstrating a novel role for the 5-HT2BRs in the regulation of complex, novelty-induced grooming activity.
