DARPP-32 mediates the actions of multiple drugs of abuse

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 32kDa (DARPP-32). Phosphorylation at Thr34 by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunction 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 a large 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. © American Association of Pharmaceutical Scientists 2008.