Pharmacological modulation of wakefulness and extracellular hypothalamic histamine release in adult male mice using TAK-925, modafinil, pitolisant, MK-8133 and Lu AF11167

Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promotion or even necessary for wake remains unclear. This study therefore measured EEG/EMG and accelerometer activity to determine sleep/wake states and locomotor activity and determined extracellular hypothalamic histamine levels using microdialysis following treatment with five wake- and sleep-modulatory compounds. We investigated the effects of three presumed wake-promoting compounds TAK-925 (danavorexton), modafinil and pitolisant as well as two presumed sleep-inducing compounds MK-8133 and Lu AF11167 in adult male mice. TAK-925 and modafinil dose-dependently prolonged wakefulness, whereas pitolisant had no effect. In contrast, TAK-925 and pitolisant increased extracellular histamine levels in hypothalamus, whereas modafinil had no effect. MK-8133 and Lu AF11167 both reduced wakefulness and decreased extracellular hypothalamic histamine levels. In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa.