Adenosine receptor–dopamine receptor interactions in the basal ganglia and their relevance for brain function

The dopamine D1 and D2 receptors are major receptors in the regulation of striatal function and striatal adenosine A1 and A2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A1–D1 heteromeric receptor complexes in the basal ganglia and prefrontal cortex and especially in the direct striatonigral–striatoentopeduncular GABA pathways. The neurochemical and behavioral findings showing antagonistic A1–D1 receptor interactions can be explained by the existence of such A1–D1 heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A2A–D2 receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A2A receptors reduces D2 receptor recognition, coupling and signaling. As a result of the A2A receptor-induced reduction of D2 receptor signaling, the activity of these GABA neurons is increased resulting in reduced motor and reward functions mediated via the indirect pathway, causing a reduced glutamate drive to the prefrontal and motor areas of the cerebral cortex. Thus, A2A receptor antagonists and A2A receptor agonists, respectively, may offer novel treatments of Parkinson's disease (reduced D2 receptor signaling) and of schizophrenia and drug addiction (increased D2 receptor signaling).