Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.

BACKGROUND AND PURPOSE Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H3 receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H4 receptor) to influence vestibular system function, using a selective H4 receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH RT-PCR was used to assess the presence of H4 receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H4 receptor modulation in the rat vestibular system. KEY RESULTS The transcripts of H4 and H3 receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H4 receptor agonist 4-methylhistamine. Thioperamide, a H3/H4 receptor antagonist, exerted effects similar to those of H3 and H4 receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H4 receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS H4 receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H4 receptors as pharmacological targets for the treatment of vestibular disorders.