The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that

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.

(GABAergic) 2 dynorphinergic neuron, which also expresses substance P (SP), and the GABAergic enkephalinergic neuron (4, 5). In fact, results obtained with in vivo techniques indicate that dopamine exerts differential effects on the two types of GABAergic efferent neurons, by acting on stimulatory D 1 receptors localized in the GABAergic SP-dynorphinergic neurons and inhibitory D 2 receptors localized in the GABAergic enkephalinergic neurons (6 -8). However, functional D 1 -like and D 2 -like receptors, as well as significant levels of D 1 and D 2 receptor mRNA expression, were detected in acutely dissociated striatonigral neurons (9). A more detailed and extensive analysis of the mRNA expression of the different receptor subtypes indicated that there is a limited subset of striatal neurons (ϳ15% of all GABAergic efferent neurons) with a mixed phenotype of GABAergic SP-dynorphinergic and GABAergic enkephalinergic neurons, with D 1 and D 2 receptors (10). This co-expression of D 1 and D 2 receptors has been confirmed in neostriatal neurons at the confocal microscopy level (11,12). George and coworkers (12, 13) have also found evidence for D 1 -D 2 receptor heteromerization (by co-immunoprecipitation) and for the generation of a unique pharmacology of the D 1 -D 2 receptor heteromer, with binding to selective ligands

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target sigma(1) receptor (sigma R-1) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma R-1-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking