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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn. (2000)
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)
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)
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)
Pelloux, Y., Everitt, B. J. & Dickinson, A. Compulsive drug seeking by rats under punishment: effects of drug taking history. Psychopharmacol. 194, 127–137 (2007)
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)
Vanderschuren, L. J. & Everitt, B. J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004)
Deroche-Gamonet, V., Belin, D. & Piazza, P. V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004)
Uylings, H. B. M., Groenewegen, J. J. & Kolb, B. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17 (2003)
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)
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)
Hare, T. A., Camerer, C. F. & Rangel, A. Self-control in decision-making involves modulation of the vmPFC valuations. Science 324, 646–648 (2009)
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)
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)
Peters, J., Kalivas, P. W. & Quirk, G. J. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn. Mem. 16, 279–288 (2009)
Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007)
Beck, H. & Yaari, Y. Plasticity of intrinsic neuronal properties in CNS disorders. Nature Rev. Neurosci. 9, 357–369 (2008)
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)
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)
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)
Zhang, F., Wang, L.-P., Boyden, E. S. & Deisseroth, K. Channelrhodopsin-2 and optical control of excitable cells. Nature Methods 3, 785–792 (2006)
Witten, I. B. et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72, 721–733 (2011)
Moussawi, K. et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nature Neurosci. 12, 182–189 (2009)
Kasanetz, F. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2012.59 (15 May 2012)
Tiffany, S. T. & Conklin, C. A. A cognitive processing model of alcohol craving and compulsive alcohol use. Addiction 95 (suppl. 2). S145–S153 (2000)
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)
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)
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)
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)
Stuber, G. D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011)
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.
The authors declare no competing financial interests.
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). https://doi.org/10.1038/nature12024
Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats
Nature Reviews Neuroscience (2020)
Journal of Neuroscience Research (2020)