Different Peas in the Same Pod: The Histaminergic Neuronal Heterogeneity

The histaminergic neuronal system is recently receiving increasing attention, as much has been learned over the past 25 years about histamine role as a neurotransmitter. Indeed, this amine is crucial in maintaining arousal and provides important contributions to regulate circadian rhythms, energy, endocrine homeostasis, motor behavior, and cognition. The extent to which these distinct physiological functions are operated by independent histamine neuronal subpopulation is unclear. In the rat brain histamine neuronal cell bodies are grouped within the tuberomamillary nucleus of the posterior hypothalamus in five clusters, E1-E5, each sending overlapping axons throughout the entire central nervous system with no strict topographical pattern. These features lead to the concept that histamine regulation of a wide range of functions in the central nervous system is achieved by the histaminergic neuronal system as a whole. However, increasing experimental evidence suggesting that the histaminergic system is organized into distinct pathways modulated by selective mechanisms challenges this view. In this review, we summarized experimental evidence supporting the heterogeneity of histamine neurons, and their organization in functionally distinct circuits impinging on separate brain regions and displaying selective control mechanisms. This implies independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections with relevant consequences for the development of specific compounds that affect only subsets of histamine neurons, thus increasing the target specificity.