Beyond head-twitch response: Acute psilocybin affects spontaneous behaviors in rats in a dose-dependent manner

Background: Psychedelics have emerged as promising pharmacological agents for treating a range of neuropsychiatric disorders. While preclinical studies have provided valuable insight into the neural mechanisms underlying their effects, systematic characterization of psychedelic effects on inherent spontaneous behaviors in animal models remains limited. Methods: In the current study, male and female Sprague-Dawley rats were administered psilocybin (0.5, 1, 1.5 mg/kg, i.p.) or its vehicle (saline). Behaviors were video recorded for subsequent analysis. In addition to the widely studied head-twitch response and wet dog shakes (HTR/WDS), five additional spontaneous behaviors that were modulated by psilocybin (immobility, rearing, grooming, sniffing/digging, and circling) were assessed. Results: Assessed behaviors showed distinct dose-response profiles in both sexes. When compared to saline, psilocybin elicited HTR/WDS following a bell-shaped curve, while immobility increased linearly, with dose. Rearing and grooming decreased markedly even at low doses, sniffing/digging declined only at higher doses, and circling increased variably across doses for each sex. Furthermore, some behaviors were correlated in a dose-dependent manner. Conclusion: Together, our findings highlight a broader range of behaviors influenced by psilocybin beyond HTR and provide a framework for identifying its neurobehavioral effects in Sprague-Dawley rats within a widely used physiologically relevant dose range.