Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Satoru Takahashi, Toshio Ohshima, Andrew Cho, Taduru Sreenath, Michael J. Iadarola, Harish C. Pant, Yong Kim, Angus C. Nairn, Roscoe O. Brady, Paul Greengard, Ashok B. Kulkarni

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Cocaine, a drug of abuse, increases synaptic dopamine levels in the striatum by blocking dopamine reuptake at axon terminals. Cyclin-dependent kinase 5 (Cdk5) and its activator p35, proteins involved in phosphorylation of substrates in postmitotic neurons, have been found to be up-regulated after chronic exposure to cocaine. To further examine the effects of Cdk5 and p35 induction on striatal dopamine signaling, we generated two independent transgenic mouse lines in which Cdk5 or p35 was overexpressed specifically in neurons. We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling. Increased Cdk5-mediated phosphorylation of dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa (DARPP-32) at Thr-75, was accompanied by decreased phosphorylation of DARPP-32 at Thr-34. Increased Cdk5-mediated phosphorylation of extracellular signalregulated kinase kinase 1 at Thr-286 was accompanied by decreased activation of extracellular signal-regulated kinase 1/2. These effects contributed to attenuation of cocaine-induced phosphorylation of cAMP response element-binding protein as well as a lesser induction of c-fos in the striatum. These results support the idea that CdkS activity is involved in altered gene expression after chronic exposure to cocaine and hence impacts the long-lasting changes in neuronal function underlying cocaine addiction.

Original languageEnglish
Pages (from-to)1737-1742
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
Publication statusPublished - 2005 Feb 1
Externally publishedYes

Keywords

  • Cocaine addiction
  • Phosphorylation
  • Striatum

ASJC Scopus subject areas

  • General

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    Takahashi, S., Ohshima, T., Cho, A., Sreenath, T., Iadarola, M. J., Pant, H. C., Kim, Y., Nairn, A. C., Brady, R. O., Greengard, P., & Kulkarni, A. B. (2005). Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1737-1742. https://doi.org/10.1073/pnas.0409456102