Histamine as an Alert Signal in the Brain

Sleep-wake behavior is a well-studied physiology in central histamine studies. Classical histamine H1 receptor antagonists, such as diphenhydramine and chlorpheniramine, promote sleep in animals and humans. Further, neuronal histamine release shows a clear circadian rhythm in parallel with wake behavior. However, the early stages of histamine-associated knockout mouse studies showed relatively small defects in normal sleep-wake control. To reassess the role of histamine in behavioral state control, this review summarizes the progress in sleep-wake studies of histamine-associated genetic mouse models and discusses the significance of histamine for characteristic aspects of wake behavior. Based on analysis of recent mouse models, we propose that neuronal histamine may serve as an alert signal in the brain, when high attention or a strong wake-drive is needed, such as during exploration, self-defense, learning, or to counteract hypersomnolent diseases. Enhanced histaminergic neurotransmission may help performance or sense of signals concerning internal or environmental dangers, like peripheral histamine from mast cells in response to allergic stimuli and inflammatory signals.