Histamine as a Global Integrator of Neurochemical Systems in the Human Brain

Histamine is a phylogenetically ancient neuromodulator with widespread projections from the tuberomammillary nucleus of the posterior hypothalamus. Rather than encoding specific perceptual, emotional, or motivational content, histamine regulates the context in which neural signals operate. Through a distinctive receptor architecture—most notably presynaptic H3 auto- and heteroreceptors—histamine interacts with all major neurochemical and neuropeptidergic systems, including dopamine, serotonin, noradrenaline, acetylcholine, glutamate, GABA, and hypothalamic peptides. In this review, we synthesise evidence across molecular, cellular, circuit, and systems neuroscience to argue that histamine functions as an interactional hub that coordinates the expression of other neuromodulatory signals. Histaminergic tone shapes monoaminergic gain, gates cholinergic cortical activation, regulates excitation–inhibition balance, and modulates neuropeptide-driven arousal, stress responsiveness, and social salience in a state-dependent manner. Rather than acting in parallel to these systems, histamine determines when their effects promote flexibility versus stability, vigilance versus recovery, and encoding versus consolidation. This interactional framework provides a unifying account of how arousal, cognition, sleep, inflammation, and behaviour are aligned, and suggests that neuropsychiatric symptoms may arise from disrupted cross-system coordination rather than isolated transmitter dysfunction.