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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleNEUROPHARMACOLOGY

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

Patrizia Giannoni, Andrew D. Medhurst, Maria Beatrice Passani, Maria Grazia Giovannini, Chiara Ballini, Laura Della Corte and Patrizio Blandina
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 164-172; DOI: https://doi.org/10.1124/jpet.109.158444
Patrizia Giannoni
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Andrew D. Medhurst
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Maria Beatrice Passani
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Maria Grazia Giovannini
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Chiara Ballini
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Laura Della Corte
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Patrizio Blandina
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Abstract

After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components.

Footnotes

  • ↵1 Current affiliation: Department of Pathology, New York University School of Medicine, New York, New York.

  • This work was supported in part by Ente Cassa di Risparmio di Firenze (I), EU COST [Grant D34]; Fondazione Monte dei Paschi (I), GlaxoSmithKline (UK) [Grant 519/0046c]; Ministero Universitá e Ricerca (I) [Grant 519MIUR068]; Universitá di Firenze (I) [Grant 519ATEN276]; and the Wellcome Trust [Grant G3340].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.158444

  • ABBREVIATIONS:

    H3R
    histamine H3 receptor
    ACh
    acetylcholine
    H4R
    histamine H4 receptor
    NBM
    nucleus basalis magnocellularis
    TMN
    tuberomammillary nuclei
    GSK189254
    6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride
    ANOVA
    analysis of variance
    HPLC
    high-performance liquid chromatography.

    • Received August 3, 2009.
    • Accepted October 8, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freel…
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Research ArticleNEUROPHARMACOLOGY

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

Patrizia Giannoni, Andrew D. Medhurst, Maria Beatrice Passani, Maria Grazia Giovannini, Chiara Ballini, Laura Della Corte and Patrizio Blandina
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 164-172; DOI: https://doi.org/10.1124/jpet.109.158444

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Research ArticleNEUROPHARMACOLOGY

Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

Patrizia Giannoni, Andrew D. Medhurst, Maria Beatrice Passani, Maria Grazia Giovannini, Chiara Ballini, Laura Della Corte and Patrizio Blandina
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 164-172; DOI: https://doi.org/10.1124/jpet.109.158444
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