Abstract
BACKGROUND AND PURPOSE: Histamine H1 receptors are highly expressed in hypothalamic neurons and mediate histaminergic modulation of several brain-controlled physiological functions, such as sleep, feeding and thermoregulation. In spite of the fact that the mouse is used as an experimental model for studying histaminergic signalling, the pharmacological characteristics of mouse H1 receptors have not been studied. In particular, selective and potent H1 receptor agonists have not been identified. EXPERIMENTAL APPROACH: Ca(2+) imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture. KEY RESULTS: The H1 receptor antagonists mepyramine and trans-triprolidine potently antagonized the activation by histamine of these receptors with IC50 values of 0.02 and 0.2 μM respectively. All H1 receptor agonists studied had relatively low potency at the H1 receptors expressed by these neurons. Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine had full-agonist activity with potencies similar to that of histamine. In contrast, 2-pyridylethylamine and betahistine showed only partial agonist activity and lower potency than histamine. The histamine receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT) had no agonist activity at the H1 receptors H1 receptors expressed by mouse preoptic/anterior hypothalamic neurons but displayed antagonist activity. CONCLUSIONS AND IMPLICATIONS: Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine were identified as full agonists of mouse H1 receptors. These results also indicated that histamine H1 receptors in mice exhibited a pharmacological profile in terms of agonism, significantly different from those of H1 receptors expressed in other species.