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Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5

Author

Listed:
  • James A. Bibb

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

  • Jingshan Chen

    (Yale University School of Medicine)

  • Jane R. Taylor

    (Yale University School of Medicine)

  • Per Svenningsson

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

  • Akinori Nishi

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
    Kurume University School of Medicine, Kurume)

  • Gretchen L. Snyder

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

  • Zhen Yan

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
    State University of New York at Buffalo)

  • Zachary K. Sagawa

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

  • Charles C. Ouimet

    (Program in Neuroscience, Florida State University)

  • Angus C. Nairn

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

  • Eric J. Nestler

    (Yale University School of Medicine
    The University of Texas Southwestern Medical Center)

  • Paul Greengard

    (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University)

Abstract

Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine re-uptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration1,2. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes1,2,3,4. One such transcription factor is ΔFosB, a protein that persists in striatum long after the end of cocaine exposure3,5. Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of ΔFosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of ΔFosB, or chronic cocaine administration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioural effects of repeated cocaine administration. Our results suggest that changes in Cdk5 levels mediated by ΔFosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.

Suggested Citation

  • James A. Bibb & Jingshan Chen & Jane R. Taylor & Per Svenningsson & Akinori Nishi & Gretchen L. Snyder & Zhen Yan & Zachary K. Sagawa & Charles C. Ouimet & Angus C. Nairn & Eric J. Nestler & Paul Gree, 2001. "Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5," Nature, Nature, vol. 410(6826), pages 376-380, March.
  • Handle: RePEc:nat:nature:v:410:y:2001:i:6826:d:10.1038_35066591
    DOI: 10.1038/35066591
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