Modulation of behavior by the histaminergic system: lessons from HDC-, H3R- and H4R-deficient mice

Histamine, which is synthesized by histidine decarboxylase (HDC), does not only modulate the immune system, but is also acting as a neurotransmitter. Histaminergic neurons project from the tuberomamillary nucleus to numerous brain regions. Activation of presynaptic H3R inhibits the release of histamine and of non-histaminergic neurotransmitters. The phenotypes of Hdc(-/-)- and Hrh3(-/-) mice comprise behaviors related to locomotor activity, memory, cognition, anxiety, circadian rhythm, pain perception, food intake and addiction. We critically discuss these phenotypes that are probably caused by global changes of the histaminergic tone rather than by an altered stimulation of a single histamine receptor subtype. Constitutive H3R activity may add another layer of complexity by causing "histamine-independent histaminergic" processes, e.g. in Hdc(-/-) mice. We also discuss the clinical relevance of H3R- and HDC-deficient mice, e.g. the role of HDC in Tourette's syndrome. Finally, this review summarizes current knowledge on possible central H4R functions. Neuronal expression of H4R, however, is discussed controversially and a systematic behavioral characterization of Hrh4(-/-) mice is still missing.