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

In the striatum, adenosine A(2A) and dopamine D-1 receptors are segreg ated in striatopallidal and striatonigral projection neurons, respecti vely. In this study, we have examined the effects of activating adenos ine A(2A) and dopamine D-1 receptors on the state of phosphorylation o f DARPP-32 (dopamine-and cyclic AMP-regulated phosphoprotein of mel. w t 32,000), a potent endogenous regulator of protein phosphatase-1 that is highly expressed in striatal medium-sized spiny neurons. In rat st riatal slices, the D-1 receptor agonist SKF 81297 and the A(2A) recept or agonist CGS 21680 transiently increased the levels of phosphorylate d DARPP-32 in a concentration-dependent manner. In the same preparatio n, the two agonists were also able to induce a significant increase in cyclic AMP formation. When striatal slices were incubated with a comb ination 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 phosphoryl ation were of similar magnitude, and were completely abolished by the cyclic AMP-dependent protein kinase inhibitor, Rp-cAMPS. The present r esults show that DARPP-32 phosphorylation in the striatum is stimulate d 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 dat a also suggest that dopamine and adenosine regulate the state of phosp horylation of DARPP-32 in distinct sub-populations of medium-sized spi ny neurons expressing dopamine D-1 and adenosine A(2A) receptors, resp ectively. (C) 1998 IBRO. Published by Elsevier Science Ltd.