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Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat

Authors

  • Patrizia Giannoni,

    1. Dipartimento di Farmacologia Preclinica e Clinica, V.le G. Pieraccini 6, Universitá di Firenze, 50139 Firenze, Italy
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    • *

      Present address: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.

    • P.G. and M.B.P. contributed equally to this article.

  • Maria-Beatrice Passani,

    1. Dipartimento di Farmacologia Preclinica e Clinica, V.le G. Pieraccini 6, Universitá di Firenze, 50139 Firenze, Italy
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    • P.G. and M.B.P. contributed equally to this article.

  • Daniele Nosi,

    1. Dipartimento di Anatomia, Istologia e Medicina Legale, Viale Morgagni, Universitá di Firenze, Firenze, Italy
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  • Paul L. Chazot,

    1. Centre for Integrative Neuroscience, School of Biological and Biomedical Sciences, Science Park, Durham University, Durham, UK
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  • Fiona C. Shenton,

    1. Centre for Integrative Neuroscience, School of Biological and Biomedical Sciences, Science Park, Durham University, Durham, UK
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  • Andrew D. Medhurst,

    1. Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
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  • Leonardo Munari,

    1. Dipartimento di Farmacologia Preclinica e Clinica, V.le G. Pieraccini 6, Universitá di Firenze, 50139 Firenze, Italy
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  • Patrizio Blandina

    1. Dipartimento di Farmacologia Preclinica e Clinica, V.le G. Pieraccini 6, Universitá di Firenze, 50139 Firenze, Italy
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Dr P. Blandina, as above.
E-mail: patrizio.blandina@unifi.it

Abstract

Histaminergic neurons of the hypothalamic tuberomammillary nuclei (TMN) send projections to the whole brain. Early anatomical studies described histaminergic neurons as a homogeneous cell group, but recent evidence indicates that histaminergic neurons are heterogeneous and organized into distinct circuits. We addressed this issue using the double-probe microdialysis in freely moving rats to investigate if two compounds acting directly onto histaminergic neurons to augment cell firing [thioperamide and bicuculline, histamine H3- and γ-aminobutyric acid (GABA)A-receptor (R) antagonists, respectively] may discriminate groups of histaminergic neurons impinging on different brain regions. Intra-hypothalamic perfusion of either drug increased histamine release from the TMN and cortex, but not from the striatum. Thioperamide, but not bicuculline, increased histamine release from the nucleus basalis magnocellularis (NBM), bicuculline but not thioperamide increased histamine release from the nucleus accumbens (NAcc). Intra-hypothalamic perfusion with thioperamide increased the time spent in wakefulness. To explore the local effects of H3-R blockade in the histaminergic projection areas, each rat was implanted with a single probe to simultaneously administer thioperamide and monitor local changes in histamine release. Thioperamide increased histamine release from the NBM and cortex significantly, but not from the NAcc or striatum. The presence of H3-Rs on histaminergic neurons was assessed using double-immunofluorescence with anti-histidine decarboxylase antibodies to identify histaminergic cells and anti-H3-R antibodies. Confocal analysis revealed that all histaminergic somata were immunopositive for the H3-R. This is the first evidence that histaminergic neurons are organized into functionally distinct circuits that influence different brain regions, and display selective control mechanisms.

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