Induction and Blockade of Adolescent Cocaine-Induced Habits

• Type of Material: Article
• Authors: Lauren M. Depoy, Emory University; Kelsey S. Zimmermann, Emory University; Paul J. Marvar, George Washington University; Shannon L Gourley, Emory University
• Language: English
• Date: 2017-04-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Society of Biological Psychiatry
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2016.09.023
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 81
• Issue: 7
• Start Page: 595
• End Page: 605
• Grant/Funding Information: This work was supported by Children's Healthcare of Atlanta, the Emory Egleston Children's Research Center, DA015040, and DA034808.; The Yerkes National Primate Research Center is supported by the Office of Research Infrastructure Programs/OD P51OD011132.
• Keywords: KINASE INHIBITOR; Arg kinase; Neurosciences; LONG-TERM POTENTIATION; DISCRIMINATIVE STIMULUS; Life Sciences & Biomedicine; DENDRITIC SPINES; Ifenprodil; ORBITOFRONTAL CORTEX; OFC; SYNAPTIC PLASTICITY; NR2B-CONTAINING NMDA RECEPTORS; Neurosciences & Neurology; Abl2; GLUTAMATERGIC PLASTICITY; PREFRONTAL CORTEX; Orbital; Response-outcome; Psychiatry; Incubation; Science & Technology; BASOLATERAL AMYGDALA
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Neuroscience

Abstract

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.