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Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking

Nature volume 496, pages 359–362 (2013)Cite this article

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Abstract

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.

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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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Intramural Research Program, National Institute on Drug Abuse, Baltimore, 21224, Maryland, USA

    Billy T. Chen, Hau-Jie Yau, Christina Hatch, Ikue Kusumoto-Yoshida & Antonello Bonci

  2. Department of Neurology, Ernest Gallo Clinic and Research Center, University of California San Francisco, San Francisco, 94608, California, USA

    Saemi L. Cho & F. Woodward Hopf

  3. Department of Neurology, University of California San Francisco, 94110, California, USA

    F. Woodward Hopf & Antonello Bonci

  4. Solomon H. Snyder Neuroscience Institute, Johns Hopkins School of Medicine, Baltimore, 21205, Maryland, USA

    Antonello Bonci

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Contributions

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.

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Correspondence to Billy T. Chen or Antonello Bonci.

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The authors declare no competing financial interests.

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Chen, B., Yau, HJ., Hatch, C. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013). https://doi.org/10.1038/nature12024

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