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 the present 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 cotransfected HEK-293 cells, H 3 (but not H 4 ) receptors were found to form heteromers with D 2 receptors. The present 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.

Background and purpose:Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1-H3 receptor heteromers and their biochemical characteristics. Experimental approach: D1-H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 receptors. Key results: Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 receptors can heteromerize. Activation of histamine H3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 receptors were co-expressed. Also, dopamine D1 receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each receptor was blocked not only by a selective antagonist but also by an antagonist of the partner receptor. Conclusions and implications: D1-H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs-independent and Gi-dependent manner. An antagonist of one of the receptor units in the D1-H3 receptor heteromer can induce conformational changes in the other receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled receptor antagonists.