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Induction and Blockade of Adolescent Cocaine-Induced Habits

  • Lauren M. DePoy
    Affiliations
    Department of Pediatrics and Department of Psychiatry, Emory University School of Medicine, Emory University, Atlanta, Georgia

    Yerkes National Primate Research Center, Graduate Program in Neuroscience, Emory University, Atlanta, Georgia
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  • Kelsey S. Zimmermann
    Affiliations
    Department of Pediatrics and Department of Psychiatry, Emory University School of Medicine, Emory University, Atlanta, Georgia

    Yerkes National Primate Research Center, Graduate Program in Neuroscience, Emory University, Atlanta, Georgia
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  • Paul J. Marvar
    Affiliations
    Department of Pharmacology and Physiology and Department of Psychiatry and Behavioral Sciences (PJM), The George Washington Institute for Neuroscience, The George Washington University, Washington, DC
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  • Shannon L. Gourley
    Correspondence
    Address correspondence to Shannon L. Gourley, Ph.D., Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta GA 30329;
    Affiliations
    Department of Pediatrics and Department of Psychiatry, Emory University School of Medicine, Emory University, Atlanta, Georgia

    Yerkes National Primate Research Center, Graduate Program in Neuroscience, Emory University, Atlanta, Georgia
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      Abstract

      Background

      Cocaine use during adolescence increases vulnerability to drug dependence and decreases the likelihood that individuals will seek treatment as adults. Understanding how early-life cocaine exposure influences decision-making processes in adulthood is thus critically important.

      Methods

      Adolescent or adult mice were exposed to subchronic cocaine, then behavioral sensitivity to changes in the predictive relationship between actions and their consequences was tested. Dendritic spines on the principal pyramidal neurons of the orbitofrontal prefrontal cortex (oPFC) were also imaged and enumerated. To determine whether cytoskeletal regulatory systems in the oPFC influenced decision-making strategies, we then inhibited the activity of Abl family and Rho kinases as well as NR2B-containing N-methyl-D-aspartate receptors. We also attempted to block the reinstatement of cocaine seeking in cocaine self-administering mice.

      Results

      Adult mice with a history of subchronic cocaine exposure in adolescence engaged habit-based response strategies at the expense of goal-directed decision-making strategies and had fewer dendritic spines in the oPFC. Inhibition of the cytoskeletal regulatory Abl family kinases in the oPFC recapitulated these neurobehavioral deficiencies, whereas Rho kinase inhibition corrected response strategies. Additionally, the NR2B-selective N-methyl-D-aspartate receptor antagonists ifenprodil and CP-101,606 blocked cocaine-induced habits; this was dependent on Abl family signaling in the oPFC. Ifenprodil also mitigated cue-induced reinstatement of cocaine seeking in mice self-administering cocaine.

      Conclusions

      We suggest that adolescent cocaine exposure confers a bias toward habit-based behavior in adulthood via long-term cellular structural modifications in the oPFC. Treatments aimed at mitigating the durable consequences of early-life cocaine use may benefit from targeting cytoskeletal regulatory systems.

      Keywords

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