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. 2005 Oct 5;7(2):E353–E360. doi: 10.1208/aapsj070235

DARPP-32 mediates the actions of multiple drugs of abuse

Per Svenningsson 1,✉, Angus C Nairn 1,2, Paul Greengard 1
PMCID: PMC2750972  PMID: 16353915

Abstract

Drugs of abuse share the ability to enhance dopaminergic neurotransmission in the dorsal and ventral striatum. The action of dopamine is modulated by additional neurotransmitters, including glutamate, serotonin and adenosine. All these neurotransmitters regulate the phosphorylation state of Dopaminal serine/threonine protein phosphatase, PP-1. Phosphorylatine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32). Phosphorylation at Thr34 by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctioon at Thr75 by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr34 also depends on the phosphorylation state of Ser97 and Ser130, which are phosphorylated by CK2 and CK1, respectively. By virtue of regulation of these 4 phosphorylation sites, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of biochemical, electrophysiological, and behavioral responses controlled by dopamine and other neurotransmitters. Importantly, there is now alarge body of evidence that supports a key role for DARPP-32-dependent signaling in mediating the actions of multiple drugs of abuse including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine.

Keywords: protein phosphorylation, psychostimulants, dopamine, striatum

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