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.
After oral administration, the nonimidazole histamine H(3) 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 H(3) 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.
Giannoni
Patrizia
P
Dipartimento di Farmacologia Preclinica e Clinica, Universitá di Firenze, Firenze, Italy.
Medhurst
Andrew D
AD
Passani
Maria Beatrice
MB
Giovannini
Maria Grazia
MG
Ballini
Chiara
C
Corte
Laura Della
LD
Blandina
Patrizio
P
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D017551:Microdialysis; D009043:Motor Activity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D001552:Benzazepines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide; D000109:Acetylcholine; D004298:Dopamine