TI - Drugs of abuse modulate the phosphorylation of ARPP-21 , a cyclic AMP -regulated phosphoprotein enriched in the basal ganglia . AB - ARPP-21 is a cyclic AMP -regulated phosphoprotein of M(r) 21 kDa that is enriched in the cell bodies and terminals of medium-sized spiny neurons in the basal ganglia . Using a new phosphorylation state-specific antibody selective for the detection of ARPP-21 phosphorylated on Ser(55) , we have demonstrated that activation of dopamine D1 receptors increased the level of ARPP-21 phosphorylation in mouse striatal slices . Conversely , activation of D2 receptors caused a large decrease in ARPP-21 phosphorylation . Treatment of mice with either methamphetamine or cocaine resulted in increased ARPP-21 phosphorylation in vivo . Studies using specific inhibitors of protein phosphatases and experiments in mice bearing a targeted deletion of the gene for DARPP-32 , a dopamine -activated inhibitor of protein phosphatase-1 , indicated that protein phosphatase-2A is primarily responsible for dephosphorylation of ARPP-21 in mouse striatum . These results demonstrate that phosphorylation and dephosphorylation of ARPP-21 are tightly regulated in the striatum . We speculate that ARPP-21 might mediate some of the physiologic effects of dopamine and certain drugs of abuse in the basal ganglia .