Changes in the histaminergic system during vestibular compensation in the cat

Abstract

To determine how the histaminergic system is implicated in vestibular compensation, we studied the changes in histidine decarboxylase (HDC; the enzyme synthesizing histamine) mRNA regulation in the tuberomammillary (TM) nuclei of cats killed 1 week, 3 weeks and 3 months after unilateral vestibular neurectomy (UVN). We also used one-and two-step bilateral vestibular neurectomized (BVN) cats to determine whether HDC mRNA regulation depended on the asymmetrical vestibular input received by the TM nuclei neurons. In addition, we analysed the HDC mRNA changes in the TM nuclei and the recovery of behavioural functions in UVN cats treated with thioperamide, a pure histaminergic drug. Finally, we quantified binding to histamine H 3 receptors (H 3 Rs) in the medial vestibular nucleus (VN) by means of a histamine H 3 R agonist ([ 3 H]N -α-methylhistamine) in order to further investigate the sites and mechanisms of action of histamine in this structure. This study shows that UVN increases HDC mRNA expression in the ipsilateral TM nucleus at 1 week. This increased expression persisted 3 weeks after UVN, and regained control values at 3 months. HDC mRNA expression was unchanged in the one-step BVN cats but showed mirror asymmetrical increases in the two-step BVN compared to the 1 week UVN cats. Three weeks' thioperamide treatment induced a bilateral HDC mRNA up-regulation in the UVN cats, which was higher than in the untreated UVN group. Binding to histamine H 3 Rs in the MVN showed a strong bilateral decrease after thioperamide treatment, while it was reduced ipsilaterally in the UVN cats. That such changes of the histaminergic system induced by vestibular lesion and treatment may play a functional role in vestibular compensation is strongly supported by the behavioural data. Indeed, spontaneous nystagmus, posture and locomotor balance were rapidly recovered in the UVN cats treated with thioperamide. These results demonstrate that changes in histamine levels are related to vestibular compensation.

Effects of Betahistine at Histamine H3Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

“…Moreover, in clinical practice, this therapeutic dose of 2 mg/kg is given for several months. In agreement with our findings, Tighilet et al (2006Tighilet et al ( , 2007 reported that this dose had no effect on histidine decarboxylase mRNA expression in control cats after a 1-or 3-week treatment. However, the same low dose acquired an enhancing effect after 3 months (Tighilet et al, 2005).…”

“…In agreement, the systemic administration of thioperamide results in a strong vestibuloplegic effect and strongly depresses the horizontal vestibular-ocular reflex gain (Yabe et al, 1993). It also accelerates the recovery of behavioral functions in the cat after unilateral vestibular neurectomy (Tighilet et al, 2006(Tighilet et al, , 2007.…”

“…However, the dose-response curve of betahistine on histamine neuron activity in lesioned animals is unknown. Its ED 50 may be lower than in controls, because imbalanced vestibular activity itself activates histamine neurons (Tighilet et al, 2006(Tighilet et al, , 2007 and the effect of the drug may synergize with this compensatory activation. Moreover, in clinical practice, this therapeutic dose of 2 mg/kg is given for several months.…”

Une nouvelle zone de neurogenèse fonctionnelle

“…Nous avons par la suite caractérisé le phénotype de ces nouveaux neurones et trouvé qu'ils exprimaient la GAD67 (glutamic acid decarboxylase 67), enzyme de synthèse du GABA. Les données recueillies en microscopie confocale ont mis en évidence une colocalisation des deux marqueurs BrdU et GAD67 ( Figure 3C) présentes en bordure du IV e ventricule ou encore de certains types d'astrocytes capables de se dédifférencier [26,27]. Une autre piste se dessine également : des progéniteurs pourraient migrer de la zone sous-ventriculaire jusqu'aux NV, en se déplaçant éventuellement le long de vaisseaux sanguins [28,29].…”

“…gliales et des astrocytes [24,25], une augmentation de l'efficacité des systèmes GABAergique, cholinergique et histaminergique [20,21,26], ainsi qu'une augmentation du nombre de neurones exprimant le BDNF, le NGF, la neurotrophine 3 (NT3) et leurs récepteurs à activité tyrosine kinase respectifs (TrkA, TrkB et TrkC) [18]. Dans une étude récente, nous avons également observé que les glucocorticoïdes, connus pour entraver la neurogenèse [27], étaient régulés négativement dans les NV après NVU [28].…”