Dopamine D₂ receptors (Rs) and adenosine A_2ARs are coexpressed on striatopallidal neurons, where they mediate opposing actions. In agreement with the idea that D₂Rs tonically inhibit GABA release from these neurons, stimulation-evoked GABA release was significantly greater from striatal/pallidal slices from D₂R null mutant (D₂R^−/−) than from wild-type (D₂R^+/+) mice. Release from heterozygous (D₂R^+/−) slices was intermediate. However, contrary to predictions that A_2AR effects would be enhanced in D₂R-deficient mice, the A_2AR agonist CGS 21680 significantly increased GABA release only from D₂R^+/+ slices. CGS 21680 modulation was observed when D₂Rs were antagonized by raclopride, suggesting that an acute absence of D₂Rs cannot explain the results. The lack of CGS 21680 modulation in the D₂R-deficient mice was also not caused by a compensatory downregulation of A_2ARs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D₂R^+/+ striatal/pallidal slices. This functional uncoupling of A_2ARs in the D₂R-deficient mice was not explained by reduced expression of G_s, G_olf, or type VI adenylyl cyclase. Locomotor activity induced by the adenosine receptor antagonist caffeine was significantly less pronounced in D₂R^−/− mice than in D₂R^+/+ and D₂R^+/− mice, further supporting the idea that D₂Rs are required for caffeine activation. Caffeine increased c-fos only in D₂R^−/− globus pallidus. The present results show that a targeted disruption of the D₂R reduces coupling of A_2ARs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D₂Rs and A_2ARs are functionally opposed and that D₂R-mediated effects normally predominate.