LAUSR

ABSTRACT The functional expression of H4 receptors (H4R) within neurons of the central nervous system has been recently reported, but their role is poorly understood. The present study aims to elucidate the role of neuronal H4R by providing the first description of the behavioural phenotype of H4R‐deficient (H4R knockout, H4R‐KO) mice. Mice lacking H4R underwent behavioural studies to evaluate locomotor activity, pain perception, anxiety, depression, memory and feeding behaviour. H4R‐KO mice showed a significant increase in ambulation in an open field as well as in exploratory activity in the absence of any modification of motor coordination. The sensitivity of mutant mice to a thermal or a mechanical stimulus was identical to that of the wild type mice, but H4R‐KO showed sensory hypersensitivity toward a condition of neuropathic pain. The lack of H4R is associated with the promotion of anxiety in the light‐dark box test. H4R‐KO mice showed an increased immobility time in the tail suspension test, experimental procedure used to evaluate the response of H4R deficient mice to a behavioural despair paradigm. Cognitive function parameters of H4R deficient mice, examined using the passive avoidance and the novel object recognition tests, were unaltered showing the lack of influence of H4R on working and recognition memory. Finally, H4R‐deficient mice showed an orectic phenotype. These results illustrate that H4R modulates various neurophysiological functions such as locomotor activity, anxiety, nociception and feeding behaviour, confirming the importance of the integrity and functionality of neuronal H4R in the histaminergic regulation of neuronal functions. Graphical abstract Figure. No Caption available. HighlightsThe behavioural phenotype of H4R‐KO has been defined.H4R modulates locomotor activity, anxiety, pain and feeding behaviour.Neuronal H4R has a prominent role in the histaminergic regulation of neuronal functions.