Activation of adenosine A 2A and dopamine D 1 receptors stimulates cyclic AMP-dependent phosphorylation of DARPP-32 in distinct populations of striatal projection neurons

Abstract

In the striatum, adenosine A 2A and dopamine D 1 receptors are segregated in striatopallidal and striatonigral projection neurons, respectively. In this study, we have examined the effects of activating adenosine A 2A and dopamine D 1 receptors on the state of phosphorylation of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000), a potent endogenous regulator of protein phosphatase-1 that is highly expressed in striatal medium-sized spiny neurons. In rat striatal slices, the D 1 receptor agonist SKF 81297 and the A 2A receptor agonist CGS 21680 transiently increased the levels of phosphorylated DARPP-32 in a concentration-dependent manner. In the same preparation, the two agonists were also able to induce a significant increase in cyclic AMP formation. When striatal slices were incubated with a combination of CGS 21680 and SKF 81297, the effects of the two agonists on both DARPP-32 phosphorylation and cyclic AMP formation were additive. The maximal effects of SKF 81297 and CGS 21680 on DARPP-32 phosphorylation were of similar magnitude, and were completely abolished by the cyclic AMP-dependent protein kinase inhibitor, Rp-cAMPS. The present results show that DARPP-32 phosphorylation in the striatum is stimulated by adenosine, acting on A 2A receptors, and dopamine, acting on D 1 receptors, and that cyclic AMP is the mediator in both cases. Our data also suggest that dopamine and adenosine regulate the state of phosphorylation of DARPP-32 in distinct sub-populations of medium-sized spiny neurons expressing dopamine D 1 and adenosine A 2A receptors, respectively.