Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D-1, dopamine D-2, and adenosine A(2A) receptors

Dopamine D-1. dopamine D-2, and adenosine A(2A) receptors are highly expres sed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamin e- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a po tent endogenous inhibitor of protein phosphatase-1, which plays an obligato ry role in dopaminergic transmission. A dose-dependent increase in the stat e of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D-2 receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosin e A(2A) receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A(2A) re ceptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D1 re ceptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/ kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 cause d by cocaine (15 mg/kg). The results indicate that, in vivo, the state of p hosphorylation of DARPP-32 and, by implication, the activity of protein pho sphatase-1 re regulated by tonic activation of D-1, D-2 and A(2A) receptors . The results also underscore the fact that the adenosine system plays a ro le in the generation of responses to dopamine D2 antagonists in vivo.