title: Induction and Blockade of Adolescent Cocaine-Induced Habits.
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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: DePoy
authors.affiliation: 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.
authors.forename: Kelsey S
authors.initials: KS
authors.lastname: Zimmermann
authors.affiliation: 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.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Marvar
authors.affiliation: 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. Electronic address: shannon.l.gourley@emory.edu.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003657:Decision Making / Q000187:drug effects*; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D058999:Drug-Seeking Behavior; D006040:Goals; D006184:Habits; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000008:administration & dosage; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D012055:Reinforcement Schedule
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D000068877:Imatinib Mesylate; C095106:traxoprodil mesylate; D016315:Proto-Oncogene Proteins c-abl; D003042:Cocaine; C010739:ifenprodil
keywords: Abl2; Arg kinase; Ifenprodil; Incubation; OFC; Orbital; Response-outcome