Vestibular compensation (the behavioural recovery that follows unilateral vestibular de-afferentation), is facilitated by histamine, and is associated with increased central histamine release and alterations in histamine H(3) receptor expression in the vestibular nuclei. However, little is known of the effects of histamine on neurotransmission in the vestibular nuclei, and the mechanisms by which histamine may influence compensation are unclear. Here we examined the modulatory effects of histaminergic agents on the release of amino acid neurotransmitters in slices of the medial vestibular nucleus (MVN) prepared from normal and labyrinthectomised rats. The release of GABA, but not glutamate, glycine or aspartate, was robustly and reproducibly evoked by a high-K(+) stimulus applied to normal MVN slices. Histamine inhibited the evoked release of GABA, both through a direct action on presynaptic H(3) receptors (presumably located on GABAergic terminals), and through a novel, indirect pathway that involved the increased release of glycine by activation of postsynaptic H(1)/H(2) receptors (presumably on glycinergic neurons). After unilateral labyrinthectomy (UL), the direct H(3) receptor-mediated inhibition of GABA release was profoundly downregulated in both ipsi-lesional and contra-lesional MVNs. This effect appeared within 25 h post-UL and persisted for at least 3 weeks post-UL. In addition, at 25 h post-UL the indirect glycinergic pathway caused a marked suppression of GABA release in the contra-lesional but not ipsi-lesional MVN, which was overcome by strychnine. Stimulation of histamine H(3) receptors at 25 h post-UL restored contra-lesional GABA release to normal, suggesting that acutely after UL H(3) receptors may strongly modulate glycinergic and GABAergic neurotransmission in the MVN. These findings are the first to demonstrate the modulatory actions of the histaminergic system on neurotransmission in the vestibular nuclei, and the changes that occur during vestibular system plasticity. During vestibular compensation, histaminergic modulation of glycine and GABA release may contribute to the rebalancing of neural activity in the vestibular nuclei of the lesioned and intact sides.