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, Paul Greengard

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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 changes1-4. 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 down-stream 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.

Original languageEnglish (US)
Pages (from-to)376-380
Number of pages5
JournalNature
Volume410
Issue number6826
DOIs
StatePublished - Mar 15 2001

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Bibb, J. A., Chen, J., Taylor, J. R., Svenningsson, P., Nishi, A., Snyder, G. L., Yan, Z., Sagawa, Z. K., Ouimet, C. C., Nairn, A. C., Nestler, E. J., & Greengard, P. (2001). Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature, 410(6826), 376-380. https://doi.org/10.1038/35066591