Functional uncoupling of adenosine A(2A) receptors and reduced response tocaffeine in mice lacking dopamine D-2 receptors

Dopamine D-2 receptors (Rs) and adenosine A(2A)Rs are coexpressed on striat opallidal neurons, where they mediate opposing actions. In agreement with t he idea that D(2)Rs tonically inhibit GABA release from these neurons, stim ulation-evoked GABA release was significantly greater from striatal/pallida l slices from D2R null mutant (D2R-/-) than from wild-type (D2R+/+) mice. R elease from heterozygous (D2R+/-) slices was intermediate. However, contrar y to predictions that A(2A)R effects would be enhanced in D2R-deficient mic e, the A(2A)R agonist CGS 21680 significantly increased GABA release only f rom D2R+/+ slices. CGS 21680 modulation was observed when D(2)Rs were antag onized by raclopride, suggesting that an acute absence of D(2)Rs cannot exp lain the results. The lack of CGS 21680 modulation in the D2R-deficient mic e was also not caused by a compensatory downregulation of A(2A)Rs in the st riatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D2R+/+ striatal/pallidal slices. This functional uncoup ling of A(2A)Rs in the D2R-deficient mice was not explained by reduced expr ession of G(s), G(olf), or type VI adenylyl cyclase. Locomotor activity ind uced by the adenosine receptor antagonist caffeine was significantly less p ronounced in D2R-/- mice than in D2R+/+ and D2R+/- mice, further supporting the idea that D(2)Rs are required for caffeine activation. Caffeine increa sed c-fos only in D2R+/+ globus pallidus. The present results show that a t argeted disruption of the D2R reduces coupling of A(2A)Rs on striatopallida l neurons and thereby responses to drugs that act on adenosine receptors. T hey also reinforce the ideas that D(2)Rs and A(2A)Rs are functionally oppos ed and that D2R-mediated effects normally predominate.