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Changes in Histamine H 3 Receptor Responsiveness in Mouse Brain
Author(s) -
Morisset S.,
Traiffort E.,
Arrang J. M.,
Schwartz J.C.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0740339.x
Subject(s) - autoreceptor , medicine , endocrinology , receptor , histamine , chemistry , pharmacology , antagonist , biology
Changes in various histamine (HA) H 3 receptor‐mediated responses and H 3 receptor binding in brain were investigated in mice receiving single or repeated administration of ciproxifan, a potent brain‐penetrating and selective H 3 receptor antagonist. Blockade of the H 3 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 ED 50 values of the drug to enhance t‐MeHA levels were increased by 5‐15 times without significant change in maximal response, indicating that H 3 autoreceptor hypersensitivity had developed. However, in synaptosomes from the cerebral cortex of these animals, the H 3 receptor‐mediated inhibition of K + ‐induced [ 3 H]HA release was not significantly modified. Subchronic administration of ciproxifan for 10 days also resulted in an increased binding of [ 125 I]iodoproxyfan to the H 3 receptor of striatal and hypothalamic membranes by 40‐54%. Hypersensitivity at H 3 somatodendritic autoreceptors and at heteroreceptors attributable to an increased number of HA binding sites could account for the various changes observed in this study.