Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 410, pages 376–380 (2001)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased expression of Cdk5 in inducible transgenic mice overexpressing ΔFosB and in rats chronically treated with cocaine.
Figure 2: Effect of Cdk5 inhibitors on locomotor behavioural response to repeated cocaine injections.
Figure 3: Increased phosphorylation of DARPP-32 by Cdk5 in inducible transgenic mice overexpressing ΔFosB and in rats chronically treated with cocaine.
Figure 4: Effects of chronic cocaine exposure on dopamine/PKA signalling in the striatum.

Similar content being viewed by others

References

  1. Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

    Article  CAS  Google Scholar 

  2. Nestler, E. J. Molecular mechanisms of opiate and cocaine addiction. Curr. Opin. Neurobiol. 7, 713–719 (1997).

    Article  CAS  Google Scholar 

  3. Hope, B. T. et al. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).

    Article  CAS  Google Scholar 

  4. Kelz, M. B. et al. Expression of the transcriptional factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Hiroi, N. et al. FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc. Natl Acad. Sci. USA 94, 10397–10402 (1997).

    Article  ADS  CAS  Google Scholar 

  6. Chen, J. et al. Transgenic animals with inducible, targeted gene expression in the brain. Mol. Pharmacol. 54, 495–503 (1998).

    Article  CAS  Google Scholar 

  7. Bibb, J. A. et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671 (1999).

    Article  ADS  CAS  Google Scholar 

  8. Snyder, G. L. et al. Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: Regulation by factors other than dopamine. J. Neurosci. 12, 3071–3083 (1992).

    Article  CAS  Google Scholar 

  9. Dulubova, I. et al. ARPP-16/ARPP-19: a highly conserved family of cAMP-regulated phosphoproteins. J. Neurochem. (in the press).

  10. Caporaso, G. et al. Dopamine and drugs of abuse modulate phosphorylation of ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in the neostriatum. Neuropharmacology 39, 1637–1644 (2000).

    Article  CAS  Google Scholar 

  11. Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 (1996).

    Article  CAS  Google Scholar 

  12. White, F. J., Hu, X. -T., Zhang, X. -F. & Wolf, M. E. Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J. Pharmacol. Exp. Ther. 273, 445–454 (1995).

    CAS  PubMed  Google Scholar 

  13. Zhang, X. -F., Hu, X. -T. & White, F. J. Whole-cell plasticity in cocaine withdrawal: Reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).

    Article  Google Scholar 

  14. Dreher, J. K. & Jackson, D. M. Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats. Brain Res. 487, 267–277 (1989).

    Article  CAS  Google Scholar 

  15. Self, D. W., Barnhart, W. J., Lehman, D. A. & Nestler, E. J. Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271, 1586–1589 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Xu, M. et al. Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice. Cell 79, 945–955 (1994).

    Article  CAS  Google Scholar 

  17. Nishi, A. et al. Amplification of dopaminergic signalling by a novel positive feedback loop. Proc. Natl Acad. Sci. USA 97, 12840–12845 (2000).

    Article  ADS  CAS  Google Scholar 

  18. Hiroi, N. et al. Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice. Eur. J. Neurosci. 11, 1114–1118 (1999).

    Article  CAS  Google Scholar 

  19. Chae, T. et al. Mice lacking p35, a neuronal specific activator of cdk5, displays cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).

    Article  CAS  Google Scholar 

  20. Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999).

    Article  ADS  CAS  Google Scholar 

  22. Zheng, M., Leung, C. L. & Liem, R. K. Region-specific expression of cyclin-dependent kinase 5 (cdk5) and its activators, p35 and p39, in the developing and adult rat central nervous system. J. Neurobiol. 35, 141–159 (1998).

    Article  CAS  Google Scholar 

  23. Le Moine, C. & Bloch, B. D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. J. Comp. Neurol. 355, 418–426 (1995).

    Article  CAS  Google Scholar 

  24. Lee, H. -K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998).

    Article  CAS  Google Scholar 

  25. Ouimet, C. C. Immunocytochemical localization of protein phosphatases and their inhibitors. Neuroprotocols 6, 84–90 (1995).

    CAS  Google Scholar 

  26. Horger, B. A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).

    Article  CAS  Google Scholar 

  27. Taylor, J. R. & Horger, B. A. Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization. Psychopharmacology 142, 31–40 (1999).

    Article  CAS  Google Scholar 

  28. Punch, L., Self, D., Nestler, E. J. & Taylor, J. R. Opposite modulation of opiate withdrawal behaviors on microinfusion of a protein kinase A inhibitor versus activator into the locus coeruleus or periaquiductal gray. J. Neurosci. 17, 8520–8527 (1997).

    Article  CAS  Google Scholar 

  29. Surmeier, D. J., Bargas, J., Hemmings, H. C. Jr, Nairn, A. C. & Greengard, P. Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron 14, 385–397 (1995).

    Article  CAS  Google Scholar 

  30. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pflüegers Arch. 391, 85–100 (1981).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Liem for Cdk5 and p35 cDNA probes; L. Meijer for roscovitine and olomoucine; and R. L. Huganir for phospho-Ser845 GluR1 antibody. We also thank V. Phantharagnsy, V. Stewart and E. Griggs for technical assistance. This work was supported by a NARSAD young investigator award (to J.A.B.), a postdoctoral fellowship from Stiftelsen för Internationalisering av högre utbildning och forskning (to P.S.), and grants from the USPHS (J.R.T., E.J.N., G.L.S., A.C.N. and P.G.).

Author information

Author notes

  1. Zhen Yan

    Present address: Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    James A. Bibb, Per Svenningsson, Akinori Nishi, Gretchen L. Snyder, Zhen Yan, Zachary K. Sagawa, Angus C. Nairn & Paul Greengard

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Jingshan Chen, Jane R. Taylor & Eric J. Nestler

  3. Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011, Japan

    Akinori Nishi

  4. Program in Neuroscience, Florida State University, Tallahassee, 32306, Florida, USA

    Charles C. Ouimet

  5. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Eric J. Nestler

Authors
  1. James A. Bibb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingshan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jane R. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Per Svenningsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akinori Nishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gretchen L. Snyder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhen Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zachary K. Sagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Charles C. Ouimet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angus C. Nairn
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eric J. Nestler
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Paul Greengard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James A. Bibb.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bibb, J., Chen, J., Taylor, J. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001). https://doi.org/10.1038/35066591

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35066591

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing