Characterization of behavioral phenotypes in histamine H4-receptor knockout mice

Histamine mediates a wide range of physiological functions through binding to four known histamine receptors. The recently cloned histamine receptor H4R is functionally expressed in the central nervous system. The aim of this study was to characterize the behavioural phenotypes of H4R knockout mice to understand the role for H4Rs in mediating histamine effects. We characterized the behaviour of H4R null and wild type mice by subjecting them to a range of behavioral tests. H4R-KO mice showed a slightly increased spontaneous mobility and exploratory activity in the hole board test, without any deficit in the rotarod test. The H4R KO mice had no cognitive impairment in the novel object recognition and passive avoidance tasks. However, KO mice differed from their WT in the mood-related behavioral tests. H4R-KO mice exhibited an anxiety-like phenotype in the light/dark box test. and a trend toward a depressive-like phenotype in the tail suspension test. We also examined whether food intake changes under a condition of food deprivation, were altered in H4R-KO mice. H4R KO mice manifested orexigenic phenotype that is characterized by increase in food intake in non food deprived mice. We have previously demonstrated that neuronal H4R is involved in neuropathic pain transmission. To validate the involvement of H4R in pain sensation, Von-Frey and Plantar tests were performed before and after spared nerve injury (SNI) in H4R-KO mice. We found that unoperated H4R-KO mice exhibited normal pain sensitivity whereas H4R-KO mice that underwent SNI surgery showed decreased ipsilateral paw withdrawal threshold, indicating the important role of H4R in the histamine-mediated modulation of pain transmission. The behavioral characterization of H4R-KO mice has demonstrated important roles of neuronal H4R in the regulation of behaviors like anxiety, regulation of food intake and pain perception, suggesting that neuronal histamine is a mediator of these neuronal functions through H4R in mice.