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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.