The dopamine D₁ and D₂ receptors are major receptors in the regulation of striatal function and striatal adenosine A₁ and A_2A 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, A_2A–D₂ receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A_2A receptors reduces D₂ receptor recognition, coupling and signaling. As a result of the A_2A 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, A_2A receptor antagonists and A_2A 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).