Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking



Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences1. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control2,3,4 could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking5,6,7,8 in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Prolonged cocaine self-administration induces compulsive cocaine seeking in a subpopulation of rats.
Figure 2: Profoundly hypoactive prelimbic cortex neurons in shock-resistant rats.
Figure 3: In vivo optogenetic stimulation of prelimbic cortex suppresses compulsive cocaine seeking.
Figure 4: In vivo optogenetic inhibition of prelimbic cortex enhances compulsive cocaine seeking.


  1. 1

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn. (2000)

  2. 2

    Naqvi, N. H. & Bechara, A. The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Struct. Funct. 214, 435–450 (2010)

    Article  Google Scholar 

  3. 3

    Goldstein, R. Z. & Volkow, N. D. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nature Rev. Neurosci. 12, 652–669 (2011)

    CAS  Article  Google Scholar 

  4. 4

    Jentsch, J. D. & Taylor, J. R. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacol. 146, 373–390 (1999)

    CAS  Article  Google Scholar 

  5. 5

    Pelloux, Y., Everitt, B. J. & Dickinson, A. Compulsive drug seeking by rats under punishment: effects of drug taking history. Psychopharmacol. 194, 127–137 (2007)

    CAS  Article  Google Scholar 

  6. 6

    Belin, D., Mar, A. C., Dalley, J. W., Robbins, T. W. & Everitt, B. J. High impulsivity predicts the switch to compulsive cocaine-taking. Science 320, 1352–1355 (2008)

    ADS  CAS  Article  Google Scholar 

  7. 7

    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 

  8. 8

    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 

  9. 9

    Uylings, H. B. M., Groenewegen, J. J. & Kolb, B. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17 (2003)

    Article  Google Scholar 

  10. 10

    Farovik, A., Dupont, L. M., Arce, M. & Eichenbaum, H. Medial prefrontal cortex supports recollection, but not familiarity, in the rat. J. Neurosci. 28, 13428–13434 (2008)

    CAS  Article  Google Scholar 

  11. 11

    Grégoire, S., Rivalan, M., Le Moine, C. & Dellu-Hagedorn, F. The synergy of working memory and inhibitory control: behavioral, pharmacological and neural functional evidences. Neurobiol. Learn. Mem. 97, 202–212 (2012)

    Article  Google Scholar 

  12. 12

    Hare, T. A., Camerer, C. F. & Rangel, A. Self-control in decision-making involves modulation of the vmPFC valuations. Science 324, 646–648 (2009)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Balleine, B. W. & O’Doherty, J. P. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacol. 35, 48–69 (2009)

    Article  Google Scholar 

  14. 14

    Jonkman, S., Mar, A. C., Dickinson, A., Robbins, T. W. & Everitt, B. J. The rat prelimbic cortex mediates inhibitory response control but not the consolidation of instrumental learning. Behav. Neurosci. 123, 875–885 (2009)

    Article  Google Scholar 

  15. 15

    Peters, J., Kalivas, P. W. & Quirk, G. J. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn. Mem. 16, 279–288 (2009)

    Article  Google Scholar 

  16. 16

    Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007)

    CAS  Article  Google Scholar 

  17. 17

    Beck, H. & Yaari, Y. Plasticity of intrinsic neuronal properties in CNS disorders. Nature Rev. Neurosci. 9, 357–369 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Yang, C. R., Seamans, J. K. & Gorelova, N. Electrophysiological and morphological properties of layers V–VI principal pyramidal cells in rat prefrontal cortex in vitro. J. Neurosci. 16, 1904–1921 (1996)

    CAS  Article  Google Scholar 

  19. 19

    Ghazizadeh, A., Ambroggi, F., Odean, N. & Fields, H. L. Prefrontal cortex mediates extinction of responding by two distinct neural mechanisms in accumbens shell. J. Neurosci. 32, 726–737 (2012)

    CAS  Article  Google Scholar 

  20. 20

    Sesack, S. R., Deutch, A. Y., Roth, R. H. & Bunney, B. S. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 290, 213–242 (1989)

    CAS  Article  Google Scholar 

  21. 21

    Zhang, F., Wang, L.-P., Boyden, E. S. & Deisseroth, K. Channelrhodopsin-2 and optical control of excitable cells. Nature Methods 3, 785–792 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Witten, I. B. et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733 (2011)

    CAS  Article  Google Scholar 

  23. 23

    Moussawi, K. et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nature Neurosci. 12, 182–189 (2009)

    CAS  Article  Google Scholar 

  24. 24

    Kasanetz, F. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol. Psychiatry (15 May 2012)

  25. 25

    Tiffany, S. T. & Conklin, C. A. A cognitive processing model of alcohol craving and compulsive alcohol use. Addiction 95 (suppl. 2). S145–S153 (2000)

    Article  Google Scholar 

  26. 26

    Martina, M., Schultz, J. H., Ehmke, H., Monyer, H. & Jonas, P. Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J. Neurosci. 18, 8111–8125 (1998)

    CAS  Article  Google Scholar 

  27. 27

    Taverna, S., Tkatch, T., Metz, A. E. & Martina, M. Differential expression of TASK channels between horizontal interneurons and pyramidal cells of rat hippocampus. J. Neurosci. 25, 9162–9170 (2005)

    CAS  Article  Google Scholar 

  28. 28

    Chen, B. T. et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron 59, 288–297 (2008)

    CAS  Article  Google Scholar 

  29. 29

    Knackstedt, L. A. & Kalivas, P. W. Extended access to cocaine self-administration enhances drug-primed reinstatement but not behavioral sensitization. J. Pharmacol. Exp. Ther. 322, 1103–1109 (2007)

    CAS  Article  Google Scholar 

  30. 30

    Stuber, G. D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011)

    CAS  Article  Google Scholar 

Download references


We thank S. Kourrich and Y. Shaham for careful reading of the manuscript. We also thank K. Deisseroth for providing the ChR2 and eNpHR3.0 vectors. This study was supported by funds from the NIDA/IRP and the State of California through the University of California at San Francisco.

Author information




B.T.C., H.-J.Y., F.W.H. and A.B. designed, discussed and planned all experiments. B.T.C., H.-J.Y., I.K.-Y., C.H. and S.L.C. performed experiments. B.T.C. and C.H. analysed data. B.T.C., F.W.H. and A.B. wrote the manuscript.

Corresponding authors

Correspondence to Billy T. Chen or Antonello Bonci.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12, Supplementary Table 1 and Supplementary References. (PDF 795 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, B., Yau, HJ., Hatch, C. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013).

Download citation

Further reading


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.


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