Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32


Zhang, Y; Svenningsson, P; Picetti, R; Schlussman, SD; Nairn, AC; Ho, A; Greengard, P; Kreek, MJ; (2006) Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32. The Journal of neuroscience, 26 (10). pp. 2645-51. ISSN 0270-6474 DOI: https://doi.org/10.1523/JNEUROSCI.3923-05.2006

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Abstract

: 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.<br/>

Item Type: Article
Keywords: Alanine/genetics/metabolism, Analysis of Variance, Animals, Behavior, Animal, Cocaine/*administration & dosage, Corpus Striatum/drug effects/metabolism, Dopamine/metabolism, Dopamine Uptake Inhibitors/*administration & dosage, Dopamine and cAMP-Regulated Phosphoprotein 32/*metabolism, Dose-Response Relationship, Drug, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microdialysis/methods, Phosphorylation, *Reinforcement (Psychology), Reinforcement Schedule, *Self Administration, Serine/*metabolism, Threonine/*metabolism, Time Factors, Alanine, genetics, metabolism, Analysis of Variance, Animals, Behavior, Animal, Cocaine, administration & dosage, Corpus Striatum, drug effects, metabolism, Dopamine, metabolism, Dopamine Uptake Inhibitors, administration & dosage, Dopamine and cAMP-Regulated Phosphoprotein 32, metabolism, Dose-Response Relationship, Drug, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microdialysis, methods, Phosphorylation, Reinforcement (Psychology), Reinforcement Schedule, Self Administration, Serine, metabolism, Threonine, metabolism, Time Factors
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Population Health (2012- )
PubMed ID: 16525043
Web of Science ID: 235868800005
URI: http://researchonline.lshtm.ac.uk/id/eprint/2680137

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