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

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 and Paul Greengard
Additional contact information
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
Gretchen L. Snyder: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
Zhen Yan: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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
Paul Greengard: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University

Nature, 2001, vol. 410, issue 6826, 376-380

Abstract: 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.

Date: 2001
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DOI: 10.1038/35066591

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