Dynamics of histamine H3 receptor antagonists on brain histamine metabolism:: do all histamine H3 receptor antagonists act at a single site?

Thioperamide, the prototypical histamine H-3 receptor antagonist, acts at the brain histamine H-3 autoreceptor to promote the release and metabolism of neuronal histamine, resulting in higher brain levels of the metabolite tele-methylhistamine. However, unlike thioperamide, several new histamine H-3 receptor antagonists enter the central nervous system (CNS), block brain histamine H-3 receptors and increase histamine release without increasing brain tele-methylhistamine levels. Experiments were performed presently in an attempt to understand these results. Consistent with previous findings, thioperamide significantly increased the content and synthesis rate of tele-methylhistamine in mouse and rat brain. In contrast, the histamine H-3 receptor antagonists GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and clobenpropit did not affect tele-methylhistamine synthesis rate in mouse whole brain. The histamine H-3 receptor ligand GT-2016 (5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one) had no effect on tele-methylhistamine levels in any rat brain region and decreased tele-methylhistamine synthesis rates in the mouse whole brain. To examine the possibility that these histamine H-3 receptor antagonists might prevent the methylation of newly released histamine, they were co-administered with thioperamide to determine their effects on the thioperamide-induced stimulation of tele-methylhistamine synthesis. GT-2016 significantly reduced the thioperamide-induced activation of tele-methylhistamine synthesis in mouse whole brain and in several regions of rat brain. Although further clarification is needed, these results suggest that some histamine H-3 receptor antagonists may promote the release of neuronal histamine, but also act to reduce histamine methylation in vivo by an unknown mechanism. (C) 2001 Elsevier Science B.V. All rights reserved.