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
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↵1 Current affiliation: Department of Pathology, New York University School of Medicine, New York, New York.
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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].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158444
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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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