Pretreatment with the psychedelic DOI mitigates LPS-induced hippocampal inflammation and behavioral impairments in mice

Abstract Background Neuroinflammation is a hallmark of numerous neuropsychiatric and neurodegenerative disorders. Psychedelics have garnered recent attention for their anti-inflammatory and neuroprotective effects. However, it remains unknown whether they can prophylactically prime immune pathways to prevent subsequent neuroinflammatory responses, and whether such effects depend on serotonin 5-HT2A receptor (5-HT2AR) signaling. Methods To characterize the inflammatory time-course, wild-type (WT) male mice received LPS (1 mg/kg, i.p.) and hippocampi were collected 2, 4, 6, 8, or 24 h later. In a separate WT cohort, basal cytokine effects of the psychedelic (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were examined following administration of varying doses or vehicle, with tissue collected 24 h later. For prophylactic studies, WT and 5-HT 2A R-KO mice were pretreated with DOI (0.3 or 1 mg/kg) or saline 24 h before LPS challenge. Behavioral assays included locomotor activity, the forced swim test (FST), and body weight monitoring. Hippocampal cytokines (IL-6, TNF-α, IFN-γ, IL-5, IL-4, IL-10, IL-13, IL-2) were quantified with a multiplex bead-based assay, and correlations between cytokine levels and FST immobility were assessed. Results LPS induced robust hippocampal increases in IL-6 and TNF-α and produced sickness-related behavioral deficits. DOI pretreatment (0.3 mg/kg, and to a lesser extent 1 m/kg) attenuated LPS-evoked IL-6 and TNF-α elevations, restored locomotor activity, reduced FST immobility, and accelerated recovery of body weight. These anti-inflammatory effects were partially preserved in 5-HT 2A R-KO mice, indicating both receptor-dependent and receptor-independent mechanisms. Notably, 5-HT 2A R-KO mice displayed exaggerated cytokine responses to LPS relative to WT animals. Correlation analyses revealed a positive association between hippocampal IL-6 levels and depressive-like behavior, whereas IL-13 and IL-2 levels were inversely correlated with immobility time in the FST. Conclusions Prophylactic DOI administration establishes a sustained neuroimmune state that mitigates subsequent hippocampal inflammation and behavioral impairments, through mechanisms that are partially dependent on 5-HT2ARs. These findings suggest that serotonergic psychedelics can prime neural-immune interactions to confer long-lasting resilience against neuroinflammatory insults, offering a potential framework for developing next-generation psychedelic therapeutics with prophylactic anti-inflammatory and neuroprotective efficacy in neuropsychiatric and neurodegenerative disorders.