IMPROVEMENT BY FUB-181, A NOVEL HISTAMINE H-3-RECEPTOR ANTAGONIST, OFLEARNING AND MEMORY IN THE ELEVATED PLUS-MAZE TEST IN MICE

Effects of FUB 181 -(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)propyl ether], a novel histamine H-3-receptor antagonist, on a scopolamine-in duced learning deficit in the elevated plus-maze test were studied in mice. FUB 181 alone (2.5 and 5 mg/kg, i.p.) ameliorated the sco polami ne-induced learning deficit in mice. This effect was antagonized by BP 2.94 (10 mg/kg, i.p.). a prodrug of (R)-alpha-methylhistamine (histam ine H-3-receptor agonist), and by ketotifen (4 mg/kg, i.p.), a histami ne H1-receptor antagonist, both penetrating the blood-brain barrier. H owever, the ameliorating effect of FUB 181 (2.5 mg/kg) was not antagon ized by either terfenadine (10 mg/kg, i.p.), a histamine H-1-receptor antagonist with poor penetration of the blood-brain barrier, or zolant idine (20 mg/kg, i.p.), a centrally effective histamine H-2-receptor a ntagonist. in a biochemical study, FUB 181 had no significant effect o n either acetylcholine or choline level in mice brain at the doses tes ted. These findings suggest that FUB 181 increases the release of hist amine by blocking presynaptic histamine H-3 autoreceptors, and that re leased histamine in turn activates postsynaptic H-1 and H-2 receptors, predominantly histamine H-1 receptors, and in this fashion improves l earning and memory in mice. Our findings also suggest that the histami nergic system may play an important role in learning and memory, and t hat FUB 181 may be a clinical candidate for the therapy of dementia.