title: Changes in histamine H3 receptor responsiveness in mouse brain.
abstract: Changes in various histamine (HA) H3 receptor-mediated responses and H3 receptor binding in brain were investigated in mice receiving single or repeated administration of ciproxifan, a potent brain-penetrating and selective H3 receptor antagonist. Blockade of the H3 autoreceptor was nearly as effective in enhancing levels of tele-methylhistamine (t-MeHA), a major HA metabolite, in brain areas when ciproxifan was administered once either at 7 a.m. or 8 p.m., in spite of the large differences of basal levels at these two phases of the circadian cycle. Blockade after a single ciproxifan administration was, however, followed by a transient decrease in striatal t-MeHA levels, possibly reflecting rapid development of autoreceptor hypersensitivity. Following a 5-day administration of ciproxifan and a 2-day drug-free period, basal t-MeHA levels were significantly decreased (approximately -20%) in three brain areas, and the ED50 values of the drug to enhance t-MeHA levels were increased by 5-15 times without significant change in maximal response, indicating that H3 autoreceptor hypersensitivity had developed. However, in synaptosomes from the cerebral cortex of these animals, the H3 receptor-mediated inhibition of K+-induced [3H]HA release was not significantly modified. Subchronic administration of ciproxifan for 10 days also resulted in an increased binding of [125I]iodoproxyfan to the H3 receptor of striatal and hypothalamic membranes by 40-54%. Hypersensitivity at H3 somatodendritic autoreceptors and at heteroreceptors attributable to an increased number of HA binding sites could account for the various changes observed in this study.
authors.affiliation: Unité de Neurobiologie et Pharmacologie Moléculaire, U.109, de l'INSERM, Centre Paul Broca, Paris, France. morisset@broca.inserm.fr
authors.forename: S
authors.initials: S
authors.lastname: Morisset
authors.forename: E
authors.initials: E
authors.lastname: Traiffort
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D011869:Radioligand Assay; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C090115:iodoproxyfan; C115705:ciproxifan; C020404:tele-methylhistamine