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.

Regulation of gene expression and cocaine reward by CREB and ΔFosB

Abstract

ΔFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of ΔFosB and the activator protein-1 (AP-1) antagonist ΔcJun. However, unlike CREB, short-term and prolonged ΔFosB induction had opposing effects on gene expression. Gene expression induced by short-term ΔFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged ΔFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly ΔFosB dependent. These findings help define the molecular functions of CREB and ΔFosB and identify clusters of genes that contribute to cocaine addiction.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Regulation of gene expression by CREB.
Figure 2: Regulation of gene expression by ΔFosB.
Figure 3: Comparison of the regulation of gene expression by ΔFosB and ΔcJun.
Figure 4: Comparison of the regulation of gene expression by CREB and ΔFosB.
Figure 5: Regulation of cocaine reward by ΔFosB and CREB.
Figure 6: Regulation of gene expression by cocaine: comparison to effects of CREB and ΔFosB.

References

  1. Nestler, E.J. Molecular basis of long-term plasticity underlying addiction. Nat. Rev. Neurosci. 2, 119–128 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609 (2001).

    Article  CAS  Google Scholar 

  4. Lonze, B.E. & Ginty, D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).

    Article  CAS  Google Scholar 

  5. Yin, J.C. & Tully, T. CREB and the formation of long-term memory. Curr. Opin. Neurobiol. 6, 264–268 (1996).

    Article  CAS  Google Scholar 

  6. Mayford, M. & Kandel, E.R. Genetic approaches to memory storage. Trends Genet. 15, 463–470 (1999).

    Article  CAS  Google Scholar 

  7. Impey, S. et al. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat. Neurosci. 1, 595–601 (1998).

    Article  CAS  Google Scholar 

  8. Duman, R.S. Synaptic plasticity and mood disorders. Mol. Psychiatry 7 (Suppl.) S29–34 (2002).

    Article  CAS  Google Scholar 

  9. Nestler, E.J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).

    Article  CAS  Google Scholar 

  10. Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).

    Article  CAS  Google Scholar 

  11. Terwilliger, R.Z., Beitner-Johnson, D., Sevarino, K.A., Crain, S.M. & Nestler, E.J. A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res. 548, 100–110 (1991).

    Article  CAS  Google Scholar 

  12. Unterwald, E.M., Cox, B.M., Kreek, M.J., Cote, T.E. & Izenwasser, S. Chronic repeated cocaine administration alters basal and opioid-regulated adenylyl cyclase activity. Synapse 15, 33–38 (1993).

    Article  CAS  Google Scholar 

  13. Turgeon, S.M., Pollack, A.E. & Fink, J.S. Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization. Brain Res. 749, 120–126 (1997).

    Article  CAS  Google Scholar 

  14. Cole, R.L., Konradi, C., Douglass, J. & Hyman, S.E. Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron 14, 813–823 (1995).

    Article  CAS  Google Scholar 

  15. Self, D.W. et al. Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behavior. J. Neurosci. 18, 1848–1859 (1998).

    Article  CAS  Google Scholar 

  16. Carlezon, W.A. et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).

    Article  CAS  Google Scholar 

  17. Pliakas, A.M. et al. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element binding protein expression in the nucleus accumbens. J. Neurosci. 21, 7397–7403 (2001).

    Article  CAS  Google Scholar 

  18. Walters, C.L. & Blendy, J.A. Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse. J. Neurosci. 21, 9438–9444 (2001).

    Article  CAS  Google Scholar 

  19. 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 

  20. Moratalla, R., Elibol, B., Vallejo, M. & Graybiel, A.M. Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal. Neuron 17, 147–156 (1996).

    Article  CAS  Google Scholar 

  21. Chen, J., Kelz, M.B., Hope, B.T., Nakabeppu, Y. & Nestler, E.J. Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments. J. Neurosci. 17, 4933–4491 (1997).

    Article  CAS  Google Scholar 

  22. Nestler, E.J., Barrot, M. & Self, D.W. DeltaFosB: a sustained molecular switch for addiction. Proc. Natl. Acad. Sci. USA 98, 11042–11046 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Colby, C.R., Whisler, K., Steffen, C., Nestler, E.J. & Self, D.W. Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine. J. Neurosci. 23, 2488–2493 (2003).

    Article  CAS  Google Scholar 

  25. Peakman, M.C. et al. Inducible, brain region-specific expression of a dominant negative mutant of c-Jun in transgenic mice decreases sensitivity to cocaine. Brain Res. 970, 73–86 (2003).

    Article  CAS  Google Scholar 

  26. Ehrlich, M.E., Sommer, J., Canas, E. & Unterwald, E.M. Periadolescent mice show enhanced DeltaFosB upregulation in response to cocaine and amphetamine. J. Neurosci. 22, 9155–9159 (2002).

    Article  CAS  Google Scholar 

  27. Simpson, J.N. & McGinty, J.F. Forskolin induces proenkephalin and preprodynorphin mRNA in rat striatum as demonstrated by in situ hybridization histochemistry. Synapse 19, 151–159 (1995).

    Article  CAS  Google Scholar 

  28. Andersson, M., Konradi, C. & Cenci, M.A. cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum. J. Neurosci. 21, 9930–9943 (2001).

    Article  CAS  Google Scholar 

  29. Ang, E. et al. Induction of nuclear factor-κB in nucleus accumbens by chronic cocaine administration. J. Neurochem. 79, 221–224 (2001).

    Article  CAS  Google Scholar 

  30. Bibb, J.A. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Sakai, N. et al. Inducible and brain region-specific CREB transgenic mice. Mol. Pharmacol. 61, 1453–1464 (2002).

    Article  CAS  Google Scholar 

  33. Newton, S.S. et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J. Neurosci. 22, 10883–10890 (2002).

    Article  CAS  Google Scholar 

  34. Shaw-Lutchman, S.Z., Impey, S., Storm, D. & Nestler, E.J. Regulation of CRE-mediated transcription in mouse brain by amphetamine. Synapse 8, 10–17 (2003).

    Article  Google Scholar 

  35. Lloyd, A., Yancheva, N. & Wasylyk, B. Transformation suppressor activity of a Jun transcription factor lacking its activation domain. Nature 352, 635–638 (1991).

    Article  CAS  Google Scholar 

  36. Brown, P.H., Kim, S.H., Wise, S.C., Sabichi, A.L. & Birrer, M.J. Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies. Cell Growth Differ. 7, 1013–1021 (1996).

    CAS  PubMed  Google Scholar 

  37. Nakabeppu, Y. & Nathans, D. A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity. Cell 64, 751–759 (1991).

    Article  CAS  Google Scholar 

  38. Yen, J., Wisdom, R.M., Tratner, I. & Verma, I.M. An alternative spliced form of FosB is a negative regulator of transcriptional activation and transformation by Fos proteins. Proc. Natl. Acad. Sci. USA 88, 5077–5081 (1991).

    Article  CAS  Google Scholar 

  39. Dobrazanski, P. et al. Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts. Mol. Cell Biol. 11, 5470–5478 (1991).

    Article  CAS  Google Scholar 

  40. Chen, J. et al. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of deltaFosB. J. Neurosci. 20, 8965–8971 (2000).

    Article  CAS  Google Scholar 

  41. Wu, X. & McMurray, C.T. Calmodulin kinase II attenuation of gene transcription by preventing cAMP response-element binding protein (CREB) dimerization and binding of the CREB-binding protein. J. Biol. Chem. 276, 1735–1741 (2001).

    Article  CAS  Google Scholar 

  42. Korutla, L. et al. Differences in expression, actions and cocaine regulation of two isoforms for the brain transcriptional regulator NAC1. Neuroscience 110, 421–429 (2002).

    Article  CAS  Google Scholar 

  43. Bannon, M.J. et al. Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Proc. Natl. Acad. Sci. USA 99, 6382–6385 (2002).

    Article  CAS  Google Scholar 

  44. O'Donovan, K.J., Tourtellotte, W.G., Millbrandt, J. & Baraban J.M. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 22, 167–173 (1999).

    Article  CAS  Google Scholar 

  45. Yuferov, V. et al. Differential gene expression in the rat caudate putamen after “binge” cocaine administration: advantage of triplicate microarray analysis. Synapse 48, 157–169 (2003).

    Article  CAS  Google Scholar 

  46. Freeman, W.M. et al. Chronic cocaine-mediated changes in non-human primate nucleus accumbens gene expression. J. Neurochem. 77, 542–549 (2001).

    Article  CAS  Google Scholar 

  47. Beinfeld, M.C., Connolly, K.J. & Pierce, R.C. Cocaine treatment increase extracellular cholecystokinin (CCK) in the nucleus accumbens shell of awake, freely moving rats, an effect that is enhanced in rats that are behaviorally sensitized to cocaine. J. Neurochem. 81, 1021–1027 (2002).

    Article  CAS  Google Scholar 

  48. Tanganelli, S., Fuxe, K., Antonelli, T., O'Connor, W.T. & Ferraro, L. Cholecystokinin/dopamine/GABA interactions in the nucleus accumbens: biochemical and functional correlates. Peptides 22, 1229–1234 (2001).

    Article  CAS  Google Scholar 

  49. Josselyn, S.A., Franco, V.P. & Vaccarino, F.J. PD-135158, A CCKB receptor antagonist, microinjected into the nucleus accumbens and the expression of conditioned rewarded behavior. Neurosci. Lett. 209, 85–88 (1996).

    Article  CAS  Google Scholar 

  50. Beurrier, C. & Malenka, R.C. Enhanced inhibition of synaptic transmission by dopamine in the nucleus accumbens during behavioral sensitization to cocaine. J. Neurosci. 22, 5817–5822 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the microarray core facility and members of the molecular psychiatry group at UT Southwestern for discussions and technical support, especially T. Macatee, W. Allman, R. Greene, M. Barrot, C. Steffen and Q. Young. Supported by grants from the National Institute on Drug Abuse, the National Institute of Mental Health and the National Institute of Alcohol Abuse and Alcoholism.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric J Nestler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

McClung, C., Nestler, E. Regulation of gene expression and cocaine reward by CREB and ΔFosB. Nat Neurosci 6, 1208–1215 (2003). https://doi.org/10.1038/nn1143

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1143

This article is cited by

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