Functional Uncoupling of Adenosine A sub(2A) Receptors and Reduced Response to Caffeine in Mice Lacking Dopamine D sub(2) Receptors

Dopamine D sub(2) receptors (Rs) and adenosine A sub(2A)Rs are coexpressed on striatopallidal neurons, where they mediate opposing actions. In agreement with the idea that D sub(2)Rs tonically inhibit GABA release from these neurons, stimulation-evoked GABA release was significantly greater from striatal/pallidal slices from D sub(2)R null mutant (D sub(2)R super(-/-)) than from wild-type (D sub(2)R super(+/+)) mice. Release from heterozygous (D sub(2)R super(+/-)) slices was intermediate. However, contrary to predictions that A sub(2A)R effects would be enhanced in D sub(2)R-deficient mice, the A sub(2A)R agonist CGS 21680 significantly increased GABA release only from D sub(2)R super(+/+) slices. CGS 21680 modulation was observed when D sub(2)Rs were antagonized by raclopride, suggesting that an acute absence of D sub(2)Rs cannot explain the results. The lack of CGS 21680 modulation in the D sub(2)R-deficient mice was also not caused by a compensatory downregulation of A sub(2A)Rs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D sub(2)R super(+/+) striatal/pallidal slices. This functional uncoupling of A sub(2A)Rs in the D sub(2)R-deficient mice was not explained by reduced expression of G sub(s), G sub(olf), or type VI adenylyl cyclase. Locomotor activity induced by the adenosine receptor antagonist caffeine was significantly less pronounced in D sub(2)R super(-/-) mice than in D sub(2)R super(+/+) and D sub(2)R super(+/-) mice, further supporting the idea that D sub(2)Rs are required for caffeine activation. Caffeine increased c-fos only in D sub(2)R super(-/-) globus pallidus. The present results show that a targeted disruption of the D sub(2)R reduces coupling of A sub(2A)Rs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D sub(2)Rs and A sub(2A)Rs are functionally opposed and that D sub(2)R-mediated effects normally predominate.