Behavioural phenotype of histamine H₄ receptor knockout mice: Focus on central neuronal functions

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.