Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D or D receptors and the histamine H receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D receptor-histamine H receptor heteromer. We have now extended this work to show the dopamine D receptor-histamine H receptor heteromer exists in the brain and serves to provide a novel link between the MAPK pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously, we found that the ability of H receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D receptors but not in D receptor-deficient mice. On the other hand, the ability of both D and H receptor antagonists to block MAPK activation induced by either D or H receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D -H receptor complexes in the striatum and, more importantly, that H receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D-H receptor heteromers. Moreover, H receptor-mediated phospho-ERK 1/2 labeling co-distributed with D receptor-containing but not with D receptor-containing striatal neurons. These results indicate that D -H receptor heteromers work as processors integrating dopamine- and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.