1. Inserm, UMR-S 839, 75005 Paris, France
2. Université Pierre et Marie Curie (UPMC), 75005 Paris, France
3. Institut du Fer à Moulin, 75005 Paris, France
4. Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
5. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA
6. Inserm, U873, CEA, 38054 Grenoble, France
7. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA
8. These authors contributed equally to this work.

Correspondence to: Jean-Antoine Girault^1,2,3 Correspondence and requests for materials should be addressed to J-A.G. (Email: girault@fer-a-moulin.inserm.fr).

Abstract

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.

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