Effects of thioperamide on the cholinergic system and the step-through passive avoidance test in mice

We investigated the effects of thioperamide, a histamine H3-receptor antagonist, on a scopolamine-induced learning deficit in the step-through passive avoidance test in mice, and on contents of acetylcholine and choline in the brain. In a behavioral study, thioperamide (20 mg/kg) alone slightly ameliorated scopolamine-induced learning deficit, and pretreatment with zolantidine, a histamine H2-receptor antagonist, significantly enhanced the ameliorating effect of thioperamide. This enhanced ameliorating effect of thioperamide was antagonized by pyrilamine, a histamine H1-receptor antagonist and (R)-alpha-methylhistamine, a histamine H3-receptor agonist, suggesting that thioperamide showed the ameliorating effect via histamine H3 receptors and/or histamine H1 receptors. In the biochemical study, thioperamide (20 mg/kg) in combination with zolantidine (20 mg/kg) significantly increased contents of choline in most of brain regions. These findings suggest that there is a close relationship between histaminergic and cholinergic systems in the brain, and that the histaminergic system may play certain important roles in learning and memory.