Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine [D.sub.1], dopamine [D.sub.2], and adenosine [A.sub.2A] receptors

Dopamine [D.sub.1], dopamine [D.sub.2], and adenosine [A.sub.2A] receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the [D.sub.2] receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine [A.sub.2A] receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective [A.sub.2A] receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase, in DARPP-32 phosphorylation was also decreased by pretreatment with the [D.sub.1] receptor 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 caused by cocaine (15 mg/kg). The results indicate that, in vivo, the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of [D.sub.1], [D.sub.2], and [A.sub.2A] receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine [D.sub.2] antagonists in vivo.