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.

Striatal microRNA controls cocaine intake through CREB signalling

Abstract

Cocaine addiction is characterized by a gradual loss of control over drug use, but the molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on cAMP response element binding protein (CREB) signalling. This action occurs through miR-212-enhanced Raf1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (transducer of regulated CREB; also known as CRTC). Our findings indicate that striatal miR-212 signalling has a key role in determining vulnerability to cocaine addiction, reveal new molecular regulators that control the complex actions of cocaine in brain reward circuitries and provide an entirely new direction for the development of anti-addiction therapeutics based on the modulation of noncoding RNAs.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Increased striatal miR-212 expression in extended access rats.
Figure 2: Dissociable effects of striatal miR-212 on cocaine intake.
Figure 3: miR-212 amplifies CREB signalling.
Figure 4: miR-212 stimulates core CREB signalling components.
Figure 5: miR-212 amplifies CREB signalling through Raf1.
Figure 6: Striatal CREB–TORC signalling controls cocaine intake.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE21901.

References

  1. McClung, C. A. & Nestler, E. J. Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33, 3–17 (2008)

    CAS  Article  Google Scholar 

  2. Kalivas, P. W. & O’Brien, C. P. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33, 166–180 (2008)

    CAS  Article  Google Scholar 

  3. Thomas, M. J., Kalivas, P. W. & Shaham, Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br. J. Pharmacol. 154, 327–342 (2008)

    CAS  Article  Google Scholar 

  4. Pulipparacharuvil, S. et al. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron 59, 621–633 (2008)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  6. Anthony, J. C., Warner, L. A. & Kessler, R. C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp. Clin. Psychopharmacol. 2, 244–268 (1994)

    Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  8. Vanderschuren, L. J. & Everitt, B. J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004)

    ADS  CAS  Article  Google Scholar 

  9. Deroche-Gamonet, V., Belin, D. & Piazza, P. V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004)

    ADS  CAS  Article  Google Scholar 

  10. Paterson, N. E. & Markou, A. Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport 14, 2229–2232 (2003)

    CAS  Article  Google Scholar 

  11. Belin, D., Balado, E., Piazza, P. V. & Deroche-Gamonet, V. Pattern of intake and drug craving predict the development of cocaine addiction-like behavior in rats. Biol. Psychiatry 65, 863–868 (2009)

    CAS  Article  Google Scholar 

  12. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    CAS  Article  Google Scholar 

  13. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006)

    ADS  CAS  Article  Google Scholar 

  14. Wayman, G. A. et al. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc. Natl Acad. Sci. USA 105, 9093–9098 (2008)

    ADS  CAS  Article  Google Scholar 

  15. Perkins, D. O., Jeffries, C. & Sullivan, P. Expanding the 'central dogma': the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia. Mol. Psychiatry 10, 69–78 (2005)

    CAS  Article  Google Scholar 

  16. Rogaev, E. I. Small RNAs in human brain development and disorders. Biochemistry (Mosc.) 70, 1404–1407 (2005)

    CAS  Article  Google Scholar 

  17. Pietrzykowski, A. Z. et al. Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol. Neuron 59, 274–287 (2008)

    CAS  Article  Google Scholar 

  18. Chandrasekar, V. & Dreyer, J. L. microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity. Mol. Cell. Neurosci. 42, 350–362 (2009)

    CAS  Article  Google Scholar 

  19. Nudelman, A. S. et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus 20, 492–498 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005)

    CAS  Article  Google Scholar 

  21. Belin, D. & Everitt, B. J. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57, 432–441 (2008)

    CAS  Article  Google Scholar 

  22. Ito, R., Dalley, J. W., Robbins, T. W. & Everitt, B. J. Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J. Neurosci. 22, 6247–6253 (2002)

    CAS  Article  Google Scholar 

  23. Vanderschuren, L. J., Di Ciano, P. & Everitt, B. J. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8670 (2005)

    CAS  Article  Google Scholar 

  24. Vo, N. et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl Acad. Sci. USA 102, 16426–16431 (2005)

    ADS  CAS  Article  Google Scholar 

  25. 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)

    CAS  Article  Google Scholar 

  26. Kocerha, J. et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc. Natl Acad. Sci. USA 106, 3507–3512 (2009)

    ADS  CAS  Article  Google Scholar 

  27. Elmén, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008)

    ADS  Article  Google Scholar 

  28. Tsang, J., Zhu, J. & van Oudenaarden, A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 26, 753–767 (2007)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  30. DiNieri, J. A. et al. Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of cAMP response element-binding protein function within the nucleus accumbens. J. Neurosci. 29, 1855–1859 (2009)

    CAS  Article  Google Scholar 

  31. Conkright, M. D. et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003)

    CAS  Article  Google Scholar 

  32. Perry, S. J. et al. Targeting of cyclic AMP degradation to β2-adrenergic receptors by β-arrestins. Science 298, 834–836 (2002)

    ADS  CAS  Article  Google Scholar 

  33. Nishi, A. et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J. Neurosci. 28, 10460–10471 (2008)

    CAS  Article  Google Scholar 

  34. Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008)

    ADS  CAS  Article  Google Scholar 

  35. Ding, Q. et al. Raf kinase activation of adenylyl cyclases: isoform-selective regulation. Mol. Pharmacol. 66, 921–928 (2004)

    CAS  PubMed  Google Scholar 

  36. Beazely, M. A., Alan, J. K. & Watts, V. J. Protein kinase C and epidermal growth factor stimulation of Raf1 potentiates adenylyl cyclase type 6 activation in intact cells. Mol. Pharmacol. 67, 250–259 (2005)

    CAS  Article  Google Scholar 

  37. Duman, R. S., Tallman, J. F. & Nestler, E. J. Acute and chronic opiate-regulation of adenylate cyclase in brain: specific effects in locus coeruleus. J. Pharmacol. Exp. Ther. 246, 1033–1039 (1988)

    CAS  PubMed  Google Scholar 

  38. Varga, E. V. et al. Involvement of Raf1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation. Eur. J. Pharmacol. 451, 101–102 (2002)

    CAS  Article  Google Scholar 

  39. King, A. J. et al. The protein kinase Pak3 positively regulates Raf1 activity through phosphorylation of serine 338. Nature 396, 180–183 (1998)

    ADS  CAS  Article  Google Scholar 

  40. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010)

    ADS  CAS  Article  Google Scholar 

  41. Hall-Jackson, C. A. et al. Paradoxical activation of Raf by a novel Raf inhibitor. Chem. Biol. 6, 559–568 (1999)

    CAS  Article  Google Scholar 

  42. Chin, P. C. et al. The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism. J. Neurochem. 90, 595–608 (2004)

    CAS  Article  Google Scholar 

  43. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008)

    ADS  CAS  Article  Google Scholar 

  44. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008)

    ADS  CAS  Article  Google Scholar 

  45. Wakioka, T. et al. Spred is a Sprouty-related suppressor of Ras signalling. Nature 412, 647–651 (2001)

    ADS  CAS  Article  Google Scholar 

  46. Brems, H. et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genet. 39, 1120–1126 (2007)

    CAS  Article  Google Scholar 

  47. Altarejos, J. Y. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nature Med. 14, 1112–1117 (2008)

    CAS  Article  Google Scholar 

  48. Kovacs, K. A. et al. TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity. Proc. Natl Acad. Sci. USA 104, 4700–4705 (2007)

    ADS  CAS  Article  Google Scholar 

  49. Zhou, Y. et al. Requirement of TORC1 for late-phase long-term potentiation in the hippocampus. PLoS ONE 1 e16 10.1371/journal.pone.0000016 (2006)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Li, S., Zhang, C., Takemori, H., Zhou, Y. & Xiong, Z. Q. TORC1 regulates activity-dependent CREB-target gene transcription and dendritic growth of developing cortical neurons. J. Neurosci. 29, 2334–2343 (2009)

    CAS  Article  Google Scholar 

  51. Caine, B. & Koob, G. F. in Behavioural Neuroscience: A Practical Approach Vol. 2 (ed. Sahgal, A.) 117–143 (IRL, 1993)

    Google Scholar 

  52. Kenny, P. J. & Markou, A. Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31, 1203–1211 (2006)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  54. Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates 3rd edn (Academic, 1997)

    Google Scholar 

  55. Silahtaroglu, A. N. et al. Detection of microRNAs in frozen tissue sections by fluorescence in situ hybridization using locked nucleic acid probes and tyramide signal amplification. Nature Protocols 2, 2520–2528 (2007)

    CAS  Article  Google Scholar 

  56. Amelio, A. L. et al. A coactivator trap identifies NONO (p54nrb) as a component of the cAMP-signaling pathway. Proc. Natl Acad. Sci. USA 104, 20314–20319 (2007)

    ADS  CAS  Article  Google Scholar 

  57. Bondeva, T., Balla, A., Varnai, P. & Balla, T. Structural determinants of Ras–Raf interaction analyzed in live cells. Mol. Biol. Cell 13, 2323–2333 (2002)

    CAS  Article  Google Scholar 

  58. Sui, G. et al. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl Acad. Sci. USA 99, 5515–5520 (2002)

    ADS  CAS  Article  Google Scholar 

  59. Conkright, M. D. et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003)

    CAS  Article  Google Scholar 

  60. Mayr, C., Hemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576–1579 (2007)

    ADS  CAS  Article  Google Scholar 

  61. Vasudevan, S., Tong, Y. & Steitz, J. A. Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Institute on Drug Abuse (NIDA) to P.J.K. and C.W., and NIDA post-doctoral awards to J.A.H. and H.-I.I. We thank M. Fallahi-Sichani for help with miRNA expression analysis and T. Balla for the Raf1 expression constructs. We also thank C. Fowler and P. Griffin for comments on the manuscript, and NIDA for supplying the cocaine used in these studies. This is manuscript 19873 from Scripps Florida.

Author information

Authors and Affiliations

Authors

Contributions

J.A.H., H.-.I.I., A.L.A., J.K., P.B. and Q.L. performed all experiments; D.W. performed microarray analysis; M.D.C. and C.W. provided essential reagents and advice; P.J.K. designed the molecular experiments; J.A.H. and P.J.K. designed the behavioural experiments, performed the statistical analyses and wrote the manuscript.

Corresponding author

Correspondence to Paul J. Kenny.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures.

This file contains Supplementary Figures 1-39 with legends. (PDF 2089 kb)

Supplementary Table 1. Supplementary Tables 1 and 2 were added on 04 August 2010

This file contains gene targets for miR-212 whose expression was knocked down. (DOC 191 kb)

Supplementary Table 2

This table contains the complete microarray data. (XLS 6404 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hollander, J., Im, HI., Amelio, A. et al. Striatal microRNA controls cocaine intake through CREB signalling. Nature 466, 197–202 (2010). https://doi.org/10.1038/nature09202

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09202

Further reading

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

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