Changes in histamine H-3 receptor responsiveness in mouse brain

Changes in various histamine (HA) H-3 receptor-mediated responses and H-3 r eceptor binding in brain were investigated in mice receiving single or repe aled administration of ciproxifan, a potent brain-penetrating and selective H-3 receptor antagonist. Blockade of the H-3 autoreceptor was nearly as ef fective in enhancing levels of tele-methylhistamine (t-MeHA), a major HA me tabolite, 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 admin istration was, however, followed by a transient decrease in striatal t-MeHA levels, possibly reflecting rapid development of autoreceptor hypersensiti vity. 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 r esponse, indicating that H-3 autoreceptor hypersensitivity had developed. H owever, in synaptosomes from the cerebral cortex of these animals, the H-3 receptor-mediated inhibition of K+-induced [H-3]HA release was not signific antly modified. Subchronic administration of ciproxifan for 10 days also re sulted in an increased binding of [I-125]iodoproxyfan to the H-3 receptor o f striatal and hypothalamic membranes by 40-54%. Hypersensitivity at H-3 so matodendritic autoreceptors and at heteroreceptors attributable to an incre ased number of HA binding sites could account for the various changes obser ved in this study.