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
2006 Journal of Neuroscience  
The reinforcing effect of cocaine is associated with increases in dopamine in the striatum. The phosphoprotein DARPP-32 (dopamineand 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
more » ... " 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 selfadministration required significantly more time in Thr34AϪ/Ϫ mice. Both Thr34A-and Ser130A-DARPP-32 mutant mice selfadministered 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.
doi:10.1523/jneurosci.3923-05.2006 pmid:16525043 fatcat:s4327bv2ancl5kf5jj7wpyf4uy