Effects of Histamine <scp> H ₃ </scp> Receptor Antagonist/Inverse Agonist Pitolisant on Temporal Prediction, Spatial Switching, and Spontaneous Locomotion in Mice

ABSTRACT Histamine receptors contribute to a wide range of brain functions, including arousal, motivation, attention, and memory, but their causal involvement in switching behavior remains insufficiently understood. Here, we examined the effects of systemic administration of pitolisant, a histamine H 3 receptor antagonist/inverse agonist, on adaptation to environmental changes in male mice using two behavioral experiments: a head‐fixed Pavlovian spatial switching temporal conditioning task and a freely‐moving open‐field assay. In the switching task, mice trained without external sensory cues rapidly adjusted both anticipatory and consummatory licking following a switch in reward location, demonstrating robust switching of temporal prediction to a new reward location. Pitolisant administration did not alter anticipatory licking, consummatory licking, or switching performance, indicating that H 3 receptor blockade does not modulate temporal prediction and switching behavior in this assay. In contrast, high‐dose pitolisant markedly reduced spontaneous locomotor activity in the open‐field and fecal output, suggesting dose‐dependent effects on motor and autonomic function. Together, these findings indicate that histamine H 3 receptor signaling exerts selective behavioral influences, with minimal impact on temporal prediction and spatial switching behavior under the present task conditions but clear effects on physiological and motor domains. This work refines the understanding of histaminergic modulation in complex behavior and highlights important considerations for interpreting the cognitive and noncognitive consequences of H 3 receptor‐targeting therapeutics.