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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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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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  1. Peter Cary

    On behalf of Yi-Yuan Tang:

    Brief meditation training induces smoking reduction
    Yi-Yuan Tang a*, Rongxiang Tang b, Michael Posner c
    a Department of Psychology & Texas Tech Neuroimaging Institute, Texas Tech University, TX 79409, USA.
    b Department of Psychology, The University of Texas at Austin, TX 78705, USA
    c Department of Psychology, University of Oregon, OR 97403, USA.
    *Correspondence to: yiyuan.tang@ttu.edu mposner@uoregon.edu; rongxiangtang@yahoo.com.

    Individuals at risk for substance abuse have deficits in self-control. Dysfunction of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) play a key role in addiction.
    Using a rat model, Chen et al. reported a marked deficit in control of drug-seeking associated with reduced prelimbic excitability. Prelimbic stimulation decreased drug-seeking behaviors, indicating a possible therapy for treating compulsive drug use1. Is there any non-pharmaceutical intervention for human addiction targeting the PFC and ACC found reduced in rats? There is evidence that meditation ameliorates negative outcomes from deficits in self-control. In a series of randomized controlled trials, we found that a form of meditation, the integrative body-mind training (IBMT), reduced stress, increased positive emotion, and improved attention and self-control after a few hours of practice compared to the same amount of relaxation training (RT). Moreover, these positive changes were accompanied by increased ACC and parasympathetic activity associated with a brain state of increased self-control2. In our recent work3, we tested whether improved self-control through IBMT would reduce craving and smoking. We advertised for volunteers wishing to reduce stress and improve performance. Among those who responded, we randomly assigned both smokers and nonsmokers to IBMT or RT groups. Both groups received 2-wk training for a total of 5 hours. Our results showed 5 hours of IBMT produced a significant reduction in smoking of 60%, while no reduction was found in RT. Meanwhile, 5 hours of IBMT also significantly reduced craving compared to RT. Resting state brain imaging showed significantly increased activity in meditation group in the ACC and PFC, brain areas related to self-control. These results suggest brief meditation training improves self-control capacity and reduces smoking and craving.
    Acknowledgments.
    This work was supported by R21DA030066, 973 Program 2012CB518200 and the Office of Naval Research.
    References
    1. Chen et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature. 496, 359-62 (2013).
    2. Tang YY, et al. Short-term meditation training improves attention and self-regulation. Proc. Natl. Acad. Sci. U.S.A 104, 17152?17156 (2007).
    3. Tang, Y.Y., Tang, R., & Posner M.I. Brief meditation training induces smoking reduction. Proc Natl Acad Sci U S A., published ahead of print August 5, 2013, doi:10.1073/pnas.1311887110

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