J. Neurochem. (2010) 113, 1046–1059. Abstract Studies in animal models of Parkinson’s disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/dopamine‐ and cAMP‐regulated phosphoprotein of Mr 32 kDa (DARPP‐32) signaling by analyzing DARPP‐32 phosphorylation at Thr34 [protein kinase A (PKA)‐site] in mouse neostriatal slices. Activation of β1‐adrenoceptors induced a rapid and transient increase in DARPP‐32 phosphorylation. Activation of α2‐adrenoceptors also induced a rapid and transient increase in DARPP‐32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of α2‐adrenoceptors attenuated, and blockade of α2‐adrenoceptors enhanced dopamine D1 and adenosine A2A receptor/DARPP‐32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of α2‐adrenoceptor blockade. Under conditions of α2‐adrenoceptor blockade, the dopamine D2 receptor‐induced decrease in DARPP‐32 phosphorylation was attenuated. Our data demonstrate that β1‐ and α2‐adrenoceptors regulate DARPP‐32 phosphorylation in neostriatal neurons. Gi activation by α2‐adrenoceptors antagonizes Gs/PKA signaling mediated by D1 and A2A receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D2 receptor/Gi signaling in striatopallidal neurons. α2‐Adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson’s disease.

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