Histamine Excites Rat Superior Vestibular Nuclear Neurons via Postsynaptic H₁and H₂Receptors in vitro

Abstract

The superior vestibular nucleus (SVN), which holds a key position in vestibulo-ocular reflexes and nystagmus, receives direct hypothalamic histaminergic innervations. By using rat brainstem slice preparations and extracellular unitary recordings, we investigated the effect of histamine on SVN neurons and the underlying receptor mechanisms. Bath application of histamine evoked an excitatory response of the SVN neurons, which was not blocked by the low-Ca²⁺/high-Mg²⁺ medium, indicating a direct postsynaptic effect of the amine. Selective histamine H₁ receptor agonist 2-pyridylethylamine and H₂ receptor agonist dimaprit, rather than VUF8430, a selective H₄ receptor agonist, mimicked the excitation of histamine on SVN neurons. In addition, selective H₁ receptor antagonist mepyramine and H₂ receptor antagonist ranitidine, but not JNJ7777120, a selective H₄ receptor antagonist, partially blocked the excitatory response of SVN neurons to histamine. Moreover, mepyramine together with ranitidine nearly totally blocked the histamine-induced excitation. Immunostainings further showed that histamine H₁ and H₂ instead of H₄ receptors existed in the SVN. These results demonstrate that histamine excites the SVN neurons via postsynaptic histamine H₁ and H₂ receptors, and suggest that the central histaminergic innervation from the hypothalamus may actively bias the SVN neuronal activity and subsequently modulate the SVN-mediated vestibular functions and gaze control.

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…control animals or siRNA-treated control cells(Ferreira et al, 2012) Extracellular recordings from SVN r Postsynaptic excitatory effect of HA on SVN neurons, sensitive to MEP and RAN, but resistant to JNJ 7777120; no effect of VUF 8430 no k.o. controls; no function of H 4 R in SVN detected(Zhuang et al, 2012) HA and IMM-induced activation of Erk1/2 MAPK pathway in RBE4 brain endothelial cells, effect sensitive to H 4 R antagonist JNJ 7777120, but resistant to ciproxifan; results confirmed in vivo in rat brain blood vessels no k.o. control; effects of H x R ligands on MAPK only moderate; IMM effect not convincing; constitutive activity of H 4 R?(Karlstedt et al, 2013) Extracellular recordings (brain slices) r HA-induced excitation of IVN neurons, sensitive to MEP and RAN, but unaffected by JNJ 7777120; HA effect mimicked by PEA and DIM, but not by VUF 8430 no k.o.…”

“…However, negative data for H 4 R expression were also obtained on the mRNA level by qPCR of MVN neurons (Zhang et al, 2013). Moreover, electrophysiological studies suggest that functional H 4 R is absent from IVN , MVN (Zhang et al, 2013) and SVN (Zhuang et al, 2012). By contrast, H 1 R and H 2 R were clearly shown to be responsible for the excitatory effect of histamine on neurons from IVN , MVN (Zhang et al, 2013) and SVN (Zhuang et al, 2012).…”

“…No H 4 R protein was detected in rat superior vestibular nucleus (SVN) (Zhuang et al, 2012), rat medial vestibular nucleus (MVN) (Zhang et al, 2013) or rat inferior vestibular nucleus (IVN) by using a rabbit anti-H 4 R polyclonal antibody. It is possible that these negative data are due to a low quality of the polyclonal antibody, as we have already discussed before in this review.…”

“…Moreover, electrophysiological studies suggest that functional H 4 R is absent from IVN , MVN (Zhang et al, 2013) and SVN (Zhuang et al, 2012). By contrast, H 1 R and H 2 R were clearly shown to be responsible for the excitatory effect of histamine on neurons from IVN , MVN (Zhang et al, 2013) and SVN (Zhuang et al, 2012). All three publications that report negative data on H 4 R in vestibular nuclei (Zhuang et al, 2012;Peng et al, 2013;Zhang et al, 2013) were published by the same laboratory and are still requiring independent verification.…”

Histamine Increases Neuronal Excitability and Sensitivity of the Lateral Vestibular Nucleus and Promotes Motor Behaviors via HCN Channel Coupled to H2 Receptor

“…As an essential part of the central histaminergic system, these histaminergic innervations on the vestibular nuclear complex, especially their physiological functions, have received increasing attention. Intriguingly, histamine exerts a uniformly excitatory effect on all four vestibular sub-nuclei (Wang and Dutia, 1995; Zhang et al, 2008, 2013; Peng et al, 2013; Zhuang et al, 2013; Yu et al, 2016). However, the receptor mechanisms underlying the histamine-induced excitation on these sub-nuclei are various (Wang and Dutia, 1995; Zhang et al, 2008, 2013; Peng et al, 2013; Zhuang et al, 2013; Yu et al, 2016).…”