Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

Effects of FUB 181 [3-(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)propyl ether], a novel histamine H₃-receptor antagonist, on a scopolamine-induced 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 scopolamine-induced learning deficit in mice. This effect was antagonized by BP 2.94 (10 mg/kg, i.p.), a prodrug of (R)-—methylhistamine (histamine H₃-receptor agonist), and by ketotifen (4 mg/kg, i.p.), a histamine H1-receptor antagonist, both penetrating the blood-brain barrier. However, the ameliorating effect of FUB 181 (2.5 mg/kg) was not antagonized by either terfenadine (10 mg/kg, i.p.), a histamine H₁-receptor antagonist with poor penetration of the blood-brain barrier, or zolantidine (20 mg/kg, i.p.), a centrally effective histamine H₂-receptor antagonist. In a biochemical study, FUB 181 had no significant effect on either acetylcholine or choline level in mice brain at the doses tested. These findings suggest that FUB 181 increases the release of histamine by blocking presynaptic histamine H₃ autoreceptors, and that released histamine in turn activates postsynaptic H₁ and H₂ receptors, predominantly histamine H₁ receptors, and in this fashion improves learning and memory in mice. Our findings also suggest that the histaminergic system may play an important role in learning and memory, and that FUB 181 may be a clinical candidate for the therapy of dementia. Received: 2 December 1997 / Accepted: 10 February 1998