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.

  • Article
  • Published:

Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse

Nature Neuroscience volume 10, pages 1029–1037 (2007)Cite this article

Abstract

A single exposure to cocaine rapidly induces the brief activation of several immediate early genes, but the role of such short-term regulation in the enduring consequences of cocaine use is poorly understood. We found that 4 h of intravenous cocaine self-administration in rats induced a transient increase in brain-derived neurotrophic factor (BDNF) and activation of TrkB-mediated signaling in the nucleus accumbens (NAc). Augmenting this dynamic regulation with five daily NAc BDNF infusions caused enduring increases in cocaine self-administration, and facilitated relapse to cocaine seeking in withdrawal. In contrast, neutralizing endogenous BDNF regulation with intra-NAc infusions of antibody to BDNF subsequently reduced cocaine self-administration and attenuated relapse. Using localized inducible BDNF knockout in mice, we found that BDNF originating from NAc neurons was necessary for maintaining increased cocaine self-administration. These findings suggest that dynamic induction and release of BDNF from NAc neurons during cocaine use promotes the development and persistence of addictive behavior.

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: Transient increases in BDNF protein and TrkB signaling in NAc following intravenous cocaine self-administration (CSA).
Figure 2: Time course for increases in BDNF and TrkB signaling in NAc shell following a single cocaine injection.
Figure 3: Dynamic regulation of NAc BDNF produces enduring increases in cocaine intake.
Figure 4: Repeated NAc BDNF infusions increase motivation for cocaine injections.
Figure 5: Dynamic regulation of NAc BDNF during SA produces enduring facilitation of relapse in cocaine withdrawal.
Figure 6: NAc BDNF and antibody to BDNF infusions fail to alter motivation for natural reward.
Figure 7: AAV-Cre–mediated BDNF knockout in NAc neurons.
Figure 8: Localized inducible knockout of BDNF in NAc neurons reduces cocaine reinforcement.

Similar content being viewed by others

References

  1. Mattson, B.J. et al. Cocaine-induced CREB phosphorylation in nucleus accumbens of cocaine-sensitized rats is enabled by enhanced activation of extracellular signal–related kinase, but not protein kinase A. J. Neurochem. 95, 1481–1494 (2005).

    Article  CAS  Google Scholar 

  2. McClung, C.A. & Nestler, E.J. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nat. Neurosci. 6, 1208–1215 (2003).

    Article  CAS  Google Scholar 

  3. Shaw-Lutchman, T.Z., Impey, S., Storm, D. & Nestler, E.J. Regulation of CRE-mediated transcription in mouse brain by amphetamine. Synapse 48, 10–17 (2003).

    Article  CAS  Google Scholar 

  4. Altar, C.A. et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389, 856–860 (1997).

    Article  CAS  Google Scholar 

  5. Gall, C.M. Regulation of brain neurotrophin expression by physiological activity. Trends Pharmacol. Sci. 13, 401–403 (1992).

    Article  CAS  Google Scholar 

  6. Guillin, O. et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411, 86–89 (2001).

    Article  CAS  Google Scholar 

  7. Seroogy, K.B. et al. Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J. Comp. Neurol. 342, 321–334 (1994).

    Article  CAS  Google Scholar 

  8. Choi, K.H., Whisler, K., Graham, D.L. & Self, D.W. Antisense-induced reduction in nucleus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement. Neuroscience 137, 373–383 (2006).

    Article  CAS  Google Scholar 

  9. Pandey, S.C., Roy, A., Zhang, H. & Xu, T. Partial deletion of the cAMP response element–binding protein gene promotes alcohol-drinking behaviors. J. Neurosci. 24, 5022–5030 (2004).

    Article  CAS  Google Scholar 

  10. Elmer, E. et al. Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures. Neuroscience 83, 351–362 (1998).

    Article  CAS  Google Scholar 

  11. Filip, M. et al. Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal. Brain Res. 1071, 218–225 (2006).

    Article  CAS  Google Scholar 

  12. Liu, Q.R. et al. Rodent BDNF genes, novel promoters, novel splice variants and regulation by cocaine. Brain Res. 1067, 1–12 (2006).

    Article  CAS  Google Scholar 

  13. Kuppers, E. & Beyer, C. Dopamine regulates brain-derived neurotrophic factor (BDNF) expression in cultured embryonic mouse striatal cells. Neuroreport 12, 1175–1179 (2001).

    Article  CAS  Google Scholar 

  14. Narita, M., Aoki, K., Takagi, M., Yajima, Y. & Suzuki, T. Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine. Neuroscience 119, 767–775 (2003).

    Article  CAS  Google Scholar 

  15. 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 

  16. Huang, E.J. & Reichardt, L.F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

    Article  CAS  Google Scholar 

  17. Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005).

    Article  CAS  Google Scholar 

  18. Grimm, J.W. et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci. 23, 742–747 (2003).

    Article  CAS  Google Scholar 

  19. Ahmed, S.H. & Koob, G.F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282, 298–300 (1998).

    Article  CAS  Google Scholar 

  20. Ahmed, S.H., Walker, J.R. & Koob, G.F. Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22, 413–421 (2000).

    Article  CAS  Google Scholar 

  21. Piazza, P.V., Deroche-Gamonent, V., Rouge-Pont, F. & Le Moal, M. Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J. Neurosci. 20, 4226–4232 (2000).

    Article  CAS  Google Scholar 

  22. Robledo, P. & Koob, G.F. Two discrete nucleus accumbens projection areas differentially mediate cocaine self-administration in the rat. Behav. Brain Res. 55, 159–166 (1993).

    Article  CAS  Google Scholar 

  23. Jaffe, J.H., Cascella, N.G., Kumor, K.M. & Sherer, M.A. Cocaine-induced cocaine craving. Psychopharmacology (Berl.) 97, 59–64 (1989).

    Article  CAS  Google Scholar 

  24. Sinha, R., Catapano, D. & O'Malley, S. Stress-induced craving and stress response in cocaine-dependent individuals. Psychopharmacology (Berl.) 142, 343–351 (1999).

    Article  CAS  Google Scholar 

  25. DSM-IV-TR. Diagnostic and Statistical Manual of Mental Disorders, 4th. Ed., Text Revision (American Psychiatric Association, Washington, DC, 2000).

  26. Castren, E., Thoenen, H. & Lindholm, D. Brain-derived neurotrophic factor messenger RNA is expressed in the septum, hypothalamus and in adrenergic brain stem nuclei of adult rat brain and is increased by osmotic stimulation in the paraventricular nucleus. Neuroscience 64, 71–80 (1995).

    Article  CAS  Google Scholar 

  27. Conner, J.M., Lauterborn, J.C., Yan, Q., Gall, C.M. & Varon, S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313 (1997).

    Article  CAS  Google Scholar 

  28. Hofer, M., Pagliusi, S.R., Hohn, A., Leibrock, J. & Barde, Y.A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 9, 2459–2464 (1990).

    Article  CAS  Google Scholar 

  29. Le Foll, B., Diaz, J. & Sokoloff, P. A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. Neuroreport 16, 175–178 (2005).

    Article  CAS  Google Scholar 

  30. Hall, F.S., Drgonova, J., Goeb, M. & Uhl, G.R. Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice. Neuropsychopharmacology 28, 1485–1490 (2003).

    Article  CAS  Google Scholar 

  31. Altar, C.A. et al. Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. Proc. Natl. Acad. Sci. USA 89, 11347–11351 (1992).

    Article  CAS  Google Scholar 

  32. Martin-Iverson, M.T., Todd, K.G. & Altar, C.A. Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine. J. Neurosci. 14, 1262–1270 (1994).

    Article  CAS  Google Scholar 

  33. Lu, L., Dempsey, J., Liu, S.Y., Bossert, J.M. & Shaham, Y. A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J. Neurosci. 24, 1604–1611 (2004).

    Article  CAS  Google Scholar 

  34. Pu, L., Liu, Q.S. & Poo, M.M. BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nat. Neurosci. 9, 605–607 (2006).

    Article  CAS  Google Scholar 

  35. Altar, C.A., Fritsche, M. & Lindsay, R.M. Cell body infusions of brain-derived neurotrophic factor increase forebrain dopamine release and serotonin metabolism determined with in vivo microdialysis. Adv. Pharmacol. 42, 915–921 (1998).

    Article  CAS  Google Scholar 

  36. Mufson, E.J. et al. Intrastriatal and intraventricular infusion of brain-derived neurotrophic factor in the cynomologous monkey: distribution, retrograde transport and colocalization with substantia nigra dopamine-containing neurons. Neuroscience 71, 179–191 (1996).

    Article  CAS  Google Scholar 

  37. Mufson, E.J. et al. Intrastriatal infusions of brain-derived neurotrophic factor: retrograde transport and colocalization with dopamine containing substantia nigra neurons in rat. Exp. Neurol. 129, 15–26 (1994).

    Article  CAS  Google Scholar 

  38. 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 

  39. Nakao, N., Kokaia, Z., Odin, P. & Lindvall, O. Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons. Exp. Neurol. 131, 1–10 (1995).

    Article  CAS  Google Scholar 

  40. Bibel, M. & Barde, Y.A. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 14, 2919–2937 (2000).

    Article  CAS  Google Scholar 

  41. Robinson, T.E., Gorny, G., Mitton, E. & Kolb, B. Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39, 257–266 (2001).

    Article  CAS  Google Scholar 

  42. Robinson, T.E. & Kolb, B. Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur. J. Neurosci. 11, 1598–1604 (1999).

    Article  CAS  Google Scholar 

  43. Rex, C.S. et al. Brain-derived neurotrophic factor promotes long-term potentiation–related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).

    Article  CAS  Google Scholar 

  44. Rios, M. et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757 (2001).

    Article  CAS  Google Scholar 

  45. Sutton, M.A. et al. Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421, 70–75 (2003).

    Article  CAS  Google Scholar 

  46. Le, Y., Miller, J.L. & Sauer, B. GFPcre fusion vectors with enhanced expression. Anal. Biochem. 270, 334–336 (1999).

    Article  CAS  Google Scholar 

  47. Hommel, J.D., Sears, R.M., Georgescu, D., Simmons, D.L. & DiLeone, R.J. Local gene knockdown in the brain using viral-mediated RNA interference. Nat. Med. 9, 1539–1544 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by United States Public Health Service Grants DA 10460, DA 08227, DA 18743, DA 016857 (D.L.G.), and the Wesley Gilliland Professorship in Biomedical Research.

Author information

Authors and Affiliations

  1. Department of Psychiatry, The Seay Center for Basic and Applied Research in Psychiatric Illness, The University of Texas Southwestern Medical Center, Dallas, 75390-9070, Texas, USA

    Danielle L Graham, Scott Edwards, Ryan K Bachtell & David W Self

  2. Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, 06508, Connecticut, USA

    Ralph J DiLeone

  3. Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, 02111, Massachusetts, USA

    Maribel Rios

Authors
  1. Danielle L Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Scott Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan K Bachtell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralph J DiLeone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maribel Rios
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David W Self
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.L.G. conducted the majority of the experiments and all of the data analysis, with assistance in tissue generation from R.K.B. and S.E. R.J.D. provided the AAV viral vectors and M.R. provided the floxed BDNF mice. D.W.S. supervised the project and co-wrote the manuscript with D.L.G.

Corresponding author

Correspondence to David W Self.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods (PDF 99 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Graham, D., Edwards, S., Bachtell, R. et al. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10, 1029–1037 (2007). https://doi.org/10.1038/nn1929

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1929

This article is cited by

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