2,5-Dimethoxy-4-methylamphetamine (DOM)-induced gait alterations in mice: Dissecting the role of 5-HT2A/2C receptor-mediated mechanisms

Psychedelics have demonstrated significant therapeutic potential in treating various psychiatric disorders; however, their effects on motor function remain poorly understood. This study investigated the impact of 2,5-dimethoxy-4-methylamphetamine (DOM), a classical phenethylamine psychedelic agent, on gait parameters in C57BL/6J mice using an active gait monitoring system. We found that 0.3–3 mg/kg DOM significantly increased locomotor velocity by enhancing stride frequency and length while reducing stance duration. These effects were accompanied by decreased plantar pressure and more concentrated paw placement patterns. High-dose DOM (10 mg/kg) suppressed voluntary locomotion, which was reversible by 5-HT_2C receptor antagonism. Pharmacological studies using subtype-selective serotonin receptor antagonists revealed that DOM's effects on gait parameters were primarily mediated through 5-HT_2A receptors. Pretreatment with 0.1 mg/kg MDL100907, but not 1 mg/kg SB242084, normalized DOM-induced gait alterations. Moreover, the antagonism of 5-HT_2A or 5-HT_2C receptor alone modified baseline gait parameters, suggesting the complex serotonergic regulation of locomotor function. These findings reveal alterations in fine gait parameters following DOM administration, expanding our understanding of the complicated effects of psychedelics.