Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

The striatum contains a high density of histamine H-3 receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H-3 and dopamine D-1 receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H-3 and dopamine D-2 receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H-3 and D-1 and also between H-3 and dopamine D-2 receptors. The selective H-3 receptor agonist imetit inhibited, while the H-3 receptor antagonist thioperamide potentiated locomotor activation induced by either the D-1 receptor agonist SKF 38393 or the D-2 receptor agonist quinpirole. High scores of locomotor activity were obtained with H-3 receptor blockade plus D-1 and D-2 receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H-3-D-2 receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H-3 receptors with several H-3 receptor agonists significantly decreased the affinity of D-2 receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H-3 (but not H-4) receptors were found to form heteromers with D-2 receptors. This study demonstrates an important role of postsynaptic H-3 receptors in the modulation of dopaminergic transmission by means of a negative modulation of D-2 receptor function. Published by Elsevier Ltd.