Cocaine disrupts action flexibility via glucocorticoid receptors
Michelle K. Sequeira,
Kathryn M. Stachowicz,
Esther H. Seo,
Sophie T. Yount,
Shannon L. Gourley
Affiliations
Michelle K. Sequeira
Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA; Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Departments of Pediatrics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, USA
Kathryn M. Stachowicz
Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Departments of Pediatrics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, USA
Esther H. Seo
Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Departments of Pediatrics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, USA
Sophie T. Yount
Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Departments of Pediatrics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA
Shannon L. Gourley
Graduate Program in Neuroscience, Emory University, Atlanta, GA, USA; Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Departments of Pediatrics and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, USA; Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA; Children’s Healthcare of Atlanta, Atlanta, GA, USA; Corresponding author
Summary: Many addictive drugs increase stress hormone levels. They also alter the propensity of organisms to prospectively select actions based on long-term consequences. We hypothesized that cocaine causes inflexible action by increasing circulating stress hormone levels, activating the glucocorticoid receptor (GR). We trained mice to generate two nose pokes for food and then required them to update action-consequence associations when one response was no longer reinforced. Cocaine delivered in adolescence or adulthood impaired the capacity of mice to update action strategies, and inhibiting CORT synthesis rescued action flexibility. Next, we reduced Nr3c1, encoding GR, in the orbitofrontal cortex (OFC), a region of the brain responsible for interlacing new information into established routines. Nr3c1 silencing preserved action flexibility and dendritic spine abundance on excitatory neurons, despite cocaine. Spines are often considered substrates for learning and memory, leading to the discovery that cocaine degrades the representation of new action memories, obstructing action flexibility.
