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

Venetia Zachariou, Véronique Sgambato-Faure, Teresa Sasaki, Per Svenningsson, Olivier Berton, Allen A. Fienberg, Angus C. Nairn, Paul Greengard, Eric J. Nestler

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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 ΔFosB 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.

Original languageEnglish
Pages (from-to)555-562
Number of pages8
JournalNeuropsychopharmacology
Volume31
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Keywords

  • Arc
  • Nucleus accumbens
  • Place preference
  • Striatum
  • c-fos
  • Δ FosB

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