Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum

Abstract

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signalregulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome

“…Previous studies with HRH3 antagonists and Hrh3 KO mice have demonstrated involvement of histamine in the regulation of addiction‐related behaviors and locomotor activity possibly via interaction with dopaminergic system (Nuutinen, Vanhanen, Pigni, & Panula, ; Vanhanen, Kinnunen, Nuutinen, & Panula, ; Vanhanen et al, ). HRH3 also regulates sensorimotor gating and dopaminergic signaling in the striatum (Kononoff Vanhanen, Nuutinen, Tuominen, & Panula, ). Direct and indirect basal ganglia pathways are differently regulated by HRH3 (Rapanelli et al, ).…”

Tourette syndrome research highlights from 2016

“…In another mouse model, knocking out the histamine H3 receptor impaired prepulse inhibition, and abolished or reduced dopaminergic signaling via both D1 and D2 receptors 53 . These results, combined with previous studies linking histamine to TS, support the development of histamine H3 receptor ligands for possible use in TS.…”

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

“…There is a large body of evidence from in‐vitro studies and in vivo studies on Hdc and Hrh3 KO mice that Hrh3 regulates striatal activity . In addition, Hrh1 and Hrh2 are also present on the soma of MSN and other striatal cells and could contribute to adjusting MSN level of activity …”

“…Hrh3 receptor activation differentially regulates intracellular signaling in medium spiny neurons of direct (expressing dopamine 1 receptors, D1‐MSN) and indirect (expressing dopamine 2 receptors, D2‐MSN) pathways and decreases dopamine release in ventral, but not dorsal striatum . Mice lacking Hrh3 receptors show abnormal prepulse inhibition and dopamine receptor signaling in striatum . In addition to modulating signaling cascades, Hrh3 is involved in differential modulation of mRNA levels of striatal opioids, dyorphin and enkephalin …”