DARPP-32 phosphorylation opposes the behavioral effects of nicotine

Hongwen Zhu, Moon Sook Lee, Fangxia Guan, Soh Agatsuma, Daniel Scott, Kevin Fabrizio, Allen A. Fienberg, Noboru Hiroi

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Background: The addictive properties of nicotine are mediated via dopaminergic pathways and their post-synaptic neurons in the striatum. Because post-synaptic neurons within the striatum contain high levels of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), we hypothesized that DARPP-32 may functionally contribute to the behavioral effects of nicotine. Methods: We examined the behavioral effects of nicotine and the phosphorylation state of DARPP-32 in wild-type (WT) and DARPP-32 knockout (KO) mice. In one experiment, we assessed voluntary nicotine intake (0-50 μg/ml) of WT and KO mice in a two-bottle choice paradigm. In a separate experiment, the motor-depressant effects of acute and repeated nicotine injections (0-.8 mg/kg, subcutaneously [SC]) were assessed. The phosphorylation of DARPP-32 at threonine34 and threonine75 were examined using Western blotting. Results: A heightened responsiveness to nicotine was seen in KO mice when compared with WT mice in oral intake and motor depression. The enhanced responsiveness in KO mice was not due to alterations in taste sensations, fluid intake, or blood nicotine or cotinine levels. Systemic injections of nicotine resulted in increased striatal DARPP-32 phosphorylation at threonine 34 and threonine75. Conclusions: DARPP-32 opposes the behavioral effects of nicotine possibly via concurrent phosphorylation at the two threonine sites.

Original languageEnglish (US)
Pages (from-to)981-989
Number of pages9
JournalBiological Psychiatry
Issue number12
StatePublished - Dec 15 2005
Externally publishedYes


  • Addiction
  • Dependence
  • Dopamine
  • PKA
  • Plasticity
  • Striatum

ASJC Scopus subject areas

  • Biological Psychiatry


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