Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action.

Zachariou V, Sgambato-Faure V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, Nairn AC, Greengard P, Nestler EJ
Neuropsychopharmacology. 2006 31 (3): 555-62

PMID: 16123776 · DOI:10.1038/sj.npp.1300832

Mice lacking DARPP-32, a striatal-enriched phosphoprotein, show abnormal behavioral and biochemical responses to cocaine, but the role of individual phosphorylation sites in DARPP-32 in these responses is unknown. We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms. In contrast, mutations of Thr75 did not affect conditioned place preference or the acute locomotor response to cocaine, but DARPP-32 Thr-75 mutants showed no locomotor sensitization in response to repeated cocaine administration. Consistent with these behavioral findings, we found that cocaine regulation of gene expression in striatum, including the acute induction of the immediate early genes c-fos and arc (activity-regulated cytoskeletal-associated gene), was abolished in DARPP-32 Thr-34 mutants, but not in Thr-75 mutants. Similarly, induction of the transcription factor DeltaFosB in the ventral striatum (nucleus accumbens) by chronic cocaine was diminished by the Thr-34, but not the Thr-75, mutation. These findings highlight distinct roles of the Thr-34 and Thr-75 phosphorylation sites of DARPP-32 in mediating short- and long-term behavioral and biochemical actions of cocaine.

MeSH Terms (17)

Animals Behavior, Animal Central Nervous System Stimulants Cocaine Conditioning, Operant Dopamine and cAMP-Regulated Phosphoprotein 32 Dopamine Uptake Inhibitors In Situ Hybridization Mice Mice, Inbred C57BL Motor Activity Mutation Neuronal Plasticity Phosphorylation Proto-Oncogene Proteins c-fos Threonine Transcription Factors

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