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The Journal of Neuroscience, March 8, 2006, 26(10):2645-2651; doi:10.1523/JNEUROSCI.3923-05.2006

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Cellular/Molecular
Cocaine Self-Administration in Mice Is Inversely Related to Phosphorylation at Thr34 (Protein Kinase A Site) and Ser130 (Kinase CK1 Site) of DARPP-32

Y. Zhang,¹ P. Svenningsson,² R. Picetti,¹ S. D. Schlussman,¹ A. C. Nairn,^2,3 A. Ho,¹ P. Greengard,² and M. J. Kreek¹

¹The Laboratory of the Biology of Addictive Diseases and ²The Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, and ³Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508

Correspondence should be addressed to Dr. Yong Zhang, The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10021. Email: zhangyo{at}mail.rockefeller.edu

The reinforcing effect of cocaine is associated with increases in dopamine in the striatum. The phosphoprotein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) has been shown to mediate the intracellular events after activation of dopamine receptors. DARPP-32 is phosphorylated at multiple sites by different protein kinases, but little is known about the functional role of these different sites. Cocaine self-administration and striatal levels of dopamine after acute "binge" cocaine administration were measured in separate lines of mice with alanine mutations introduced into DARPP-32 at either Thr34 (protein kinase A site, Thr34A), Thr75, (cyclin-dependent kinase 5 site, Thr75A), Ser97 (kinase CK2 site, Ser97A), or Ser130 (kinase CK1 site, Ser130A). Acquisition of stable cocaine self-administration required significantly more time in Thr34A–/– mice. Both Thr34A- and Ser130A-DARPP-32 mutant mice self-administered more cocaine than their respective wild-type controls. Also, cocaine-induced increases of dopamine in dorsal striatum were attenuated in the Thr34A- and Ser130A-DARPP-32 phosphomutant mice compared with wild-type mice. Notably, levels of P-Thr34- and P-Ser130-DARPP-32 were reduced after self-administration of cocaine in wild-type mice. Thus, phosphorylation states of Thr34- and Ser130-DARPP-32 play important roles in modulating the reinforcing effects of cocaine.

Key words: DARPP-32; phosphorylation; mutation; cocaine; self-administration; dopamine

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Received May 12, 2005; revised Jan. 11, 2006; accepted Jan. 13, 2006.

Correspondence should be addressed to Dr. Yong Zhang, The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10021. Email: zhangyo{at}mail.rockefeller.edu

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