Functional pharmacology of H₁ histamine receptors expressed in mouse preoptic/anterior hypothalamic neurons

Abstract

BACKGROUND AND PURPOSEHistamine 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 Ca2+ imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture. KEY RESULTSThe 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 IMPLICATIONSMethylhistaprodifen 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.

Histamine inhibits the melanin‐concentrating hormone system: implications for sleep and arousal

“…Consistent with our in situ hybridization data showing that MCH neurons do not express H1R or H2R, a H1 agonist, 2‐pyridylethylamine (100 μ m ) (Tabarean, ) and a selective H2 agonist, amthamine (5 μ m ) (Threlfell et al . ) had no effects on resting membrane potentials, input resistance, or rheobases of the recorded MCH+ cells (see online Supporting information Fig.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…H 1 receptor activation excites neurons in most brain regions, including brain stem (Lin et al, 1996;Barbara et al, 2002;Korotkova et al, 2005), hypothalamus Histamine Receptors (Tabarean, 2013), thalamus Soria-Jasso et al, 1997;Zhou et al, 2006), amygdala, septum (Gorelova and Reiner, 1996;Xu et al, 2004), hippocampus (Selbach et al, 1997;Manahan-Vaughan et al, 1998), olfactory bulb (Jahn et al, 1995), and cortex (Reiner and Kamondi, 1994) through an increase of [Ca 2+ ] i . Figure 6 illustrates examples of inward current and increased firing frequency.…”

Sleep- and Wake-Like States in Small Networks In Vivo and In Vitro

“…Most studies addressing the role of the ventrolateral preoptic area (VLPO) in sleep regulation have utilised Fos immunoreactivity experiments (Sherin et al, 1996) or electrophysiological recordings in slice or neuronal cultures (Tabarean, 2013). VLPO neurons have been shown to produce powerful low-threshold Ca2+ spikes (LTS), and are inhibited by the major wakefulness related neurotransmitters such as noradrenaline.…”