title: Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences.
abstract: Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called 'reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, 'stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in 'stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure.
authors: Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, GA, USA.|Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.|Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA.
authors: L M
authors: LM
authors: DePoy
authors: Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, GA, USA.|Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
authors: A G
authors: AG
authors: Allen
authors: Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, GA, USA.|Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.|Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA.|Department of Psychiatry and Behavioral Sciences, Emory School of Medicine, Emory University, Atlanta, GA, USA.
authors: S L
authors: SL
authors: Gourley
mesh_terms: D000367:Age Factors; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological; D003657:Decision Making / Q000187:drug effects*; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D047309:Flavones / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000473:pathology; D020813:Receptor, trkB / Q000819:agonists; D012201:Reward; D012646:Self Administration
chemical_list: C485383:6,7-dihydroxyflavone; D018765:Dopamine Uptake Inhibitors; D047309:Flavones; D058786:GABA-B Receptor Agonists; D020813:Receptor, trkB; D001418:Baclofen; D003042:Cocaine