title: Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability.
abstract: OBJECTIVE
  Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H(3) receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H(4) receptor) to influence vestibular system function, using a selective H(4) receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584.
  
  
  METHODS
  RT-PCR was used to assess the presence of H(4) 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 H(4) receptor modulation in the rat vestibular system.
  
  
  RESULTS
  The transcripts of H(4) and H(3) 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 H(4) receptor agonist 4-methylhistamine. Thioperamide, a H(3) /H(4) receptor antagonist, exerted effects similar to those of H(3) and H(4) receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H(4) receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects.
  
  
  CONCLUSIONS
  H(4) receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H(4) receptors as pharmacological targets for the treatment of vestibular disorders.
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Hopital St Eloi, Montpellier, France. desmad@univ-montp2.fr
authors.forename: G
authors.initials: G
authors.lastname: Desmadryl
authors.forename: S
authors.initials: S
authors.lastname: Gaboyard-Niay
authors.forename: A
authors.initials: A
authors.lastname: Brugeaud
authors.forename: C
authors.initials: C
authors.lastname: Travo
authors.forename: A
authors.initials: A
authors.lastname: Broussy
authors.forename: A
authors.initials: A
authors.lastname: Saleur
authors.forename: J
authors.initials: J
authors.lastname: Dyhrfjeld-Johnsen
authors.forename: E
authors.initials: E
authors.lastname: Wersinger
authors.forename: C
authors.initials: C
authors.lastname: Chabbert
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001621:Betahistine / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D011968:Receptors, Histamine / Q000502:physiology*; D000074040:Receptors, Histamine H4; D014725:Vestibular Nerve / Q000166:cytology / Q000502:physiology*
chemical_list: D001562:Benzimidazoles; D017442:Histamine Agonists; D006633:Histamine Antagonists; D054828:Histamine H3 Antagonists; C498828:Hrh4 protein, rat; D007211:Indoles; C506811:JNJ 10191584; D010879:Piperazines; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; C052075:thioperamide; D001621:Betahistine