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

Abstract

The dopamine D 1 and D 2 receptors are major receptors in the regulation of striatal function and striatal adenosine A 1 and A 2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A 1–D 1 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 A 1–D 1 receptor interactions can be explained by the existence of such A 1–D 1 heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A 2A–D 2 receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A 2A receptors reduces D 2 receptor recognition, coupling and signaling. As a result of the A 2A receptor-induced reduction of D 2 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, A 2A receptor antagonists and A 2A receptor agonists, respectively, may offer novel treatments of Parkinson's disease (reduced D 2 receptor signaling) and of schizophrenia and drug addiction (increased D 2 receptor signaling).