Acute DOI treatment evokes dose and species-dependent locomotor effects on the elevated plus maze

Recent evidence suggests that psychedelics hold promise in treating a range of neuropsychiatric disorders, highlighting the need to better understand their broader behavioral effects. Many animal-based behavioral assays related to mood, like anxiety and despair-like behavior, highly depend on locomotor activity. However, the influence of psychedelics on movement, especially in emotionally salient contexts, remains underexplored. While general locomotor activity can be monitored in the home cage, assessing movement in novel environments is critical for interpreting behaviors shaped by context and novelty. In this study, we examine the effects of the serotonergic psychedelic, DOI, on locomotor activity using the elevated plus maze (EPM), a conventionally used conflict-based anxiety maze. We find that DOI alters locomotor behavior in rats in a dose-dependent manner, and these changes are closely correlated with changes in anxiety-like behavior on the EPM. Notably, we observe species- and strain-specific differences in the DOI-evoked influence on spontaneous motor activity. While Sprague-Dawley rats and 129S6/SvEv mice exhibit reduced movement in response to 1 mg/kg DOI, C57BL/6J mice show increased movement at the same dose. The modulation of locomotor activity, like the observed anxiety-related effects, appears to be driven by the serotonin 2A receptor (5-HT_2A R), as noted by the absence of DOI-evoked locomotor changes in 5-HT_2A R knockout (KO) mice. These findings highlight the importance of considering the impact of serotonergic psychedelics on both spontaneous and context-dependent locomotion whilst interpreting mood-related behavioral responses in novelty-dependent, conflict-based approach-avoidance tasks.