In a companion paper (Serafin et al. 1992) we have demonstrated in vitro that histamine depolarizes three previously described medial vestibular nucleus neuron (MVNn) types (Serafin et al. 1991a, b). It has also been shown that this effect was exclusively mediated through postsynaptic H2 receptors. All the same, the eventual contribution of presynaptic H3 receptors to the physiological response of the MVNn to histamine remained an open question since, during the slicing procedure, any histaminergic axons projecting to the vestibular nuclei would have been interrupted. This rendered our study of H3-mediated effects of histamine difficult. Hence, in the present in vivo study our aim was three-fold: (1) to investigate the presence of H3 receptors at the vestibular nuclei level; (2) to evaluate the functional importance of MVNn H2 receptors; and (3) to explore whether H3 ligands, when injected intraperitoneally (i.p.), could modulate dynamic vestibular functions. In order to address the first two questions, we investigated postural changes induced by perfusion of the guinea-pig's vestibular nuclear complex with specific ligands of the H2 and H3 receptors. Our data extend the conclusions of our in vitro study and suggest that lateral vestibular nuclei neurons and the MVNn are endowed with both H2 and H3 receptors. Our results indicate furthermore that histamine can modulate, quite effectively, static vestibular reflexes. Finally, the present study demonstrates that i.p. injection of thioperamide, an H3 antagonist, induces a significant decrease in the horizontal vestibular-ocular reflex gain and, by contrast to most of the clinically used antihistaminics, has no detrimental effect on the alertness level. Our results may thus lead to clinical testing and use of H3 antagonists as antivertigo or anti motion-sickness drugs.