¹University of Claude Bernard, INSERM U1208, Bron, France, ²University of Toulouse, Research Center on Animal Cognition (CRCA), Toulouse, France

Background: ^​Recent clinical findings have highlighted the therapeutic potential of serotonergic psychedelics, including lysergic acid diethylamide (LSD), in the treatment of affective disorders. Despite these advances, the mechanisms driving their beneficial effects remain partially understood.

Aims & Objectives: This study sought to assess the prophylactic effects of LSD in rodent models of inflammation-induced depressive-like behaviors. Given LSD’s high affinity for the 5-HT2B receptor, a target implicated in both inflammatory processes and mood regulation, we further examined whether this receptor contributes to LSD’s antidepressant-like actions.

Method: ​​​​Male mice received a single intraperitoneal (i.p.) dose of LSD (0.15 mg/kg) or saline 24 hours before administration of lipopolysaccharide (LPS; 5.0 mg/kg, i.p.). Male rats were administered a single dose of LSD (0.05 mg/kg, i.p.) or saline five days prior to injection of polyinosinic:polycytidylic acid (poly(I:C); 3.0 mg/kg, i.p.). To investigate the involvement of the 5-HT2B receptor, the selective 5-HT2B antagonist RS-127445 (0.16 mg/kg, i.p.) was used to modulate LSD’s effects, whereas the preferential 5-HT2B agonist BW723C86 was used for comparison. Depressive-like behaviors were assessed using the forced swim test (FST) and/or the sucrose preference test (SPT).

Results: In mice, LSD pretreatment significantly attenuated LPS-induced long-lasting increases in immobility during the FST and restored sucrose preference in the SPT. BW723C86 failed to alter significantly the latter effects. In rats, LSD pretreatment likewise reduced poly(I:C)-induced immobility in the FST. Importantly in both mice and rats, RS-127445 did not modify these behavioral outcomes.

Discussion & Conclusions: LSD elicited robust and long-lasting antidepressant-like effects in rodent models of inflammation-associated depression. These effects appear to occur independently of 5-HT2B receptor activation, indicating that alternative mechanisms may mediate LSD’s mood-regulating properties. Such pathways may provide promising and potentially safer therapeutic strategies for treating inflammation-related depressive disorders.