title: Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.
abstract: Prefrontal cortical (PFC)-hippocampal-striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability.
  
  
  
  In healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes.
  
  
  
  Rats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n = 80) or nicotine self-administration (experiment 2; n = 12).
  
  
  
  In experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio ("FLETR"; p < 0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R2= 0.14, p < 0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R2= 0.47, p < 0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement.
  
  
  
  These findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC-hippocampal-striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Kalyan N
authors.initials: KN
authors.lastname: Rao
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.|IU Neuroscience Research Center, Indianapolis, IN, USA.
authors.forename: Alena M
authors.initials: AM
authors.lastname: Sentir
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Engleman
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.|Adolescent Dual Diagnosis Clinic, Riley Hospital for Children at IU Health, Indianapolis, IN, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Hulvershorn
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Psychiatry, Psychotic Disorders Program at IU, Indiana University School of Medicine, Indiana University Prevention and Recovery Center for Early Psychosis (PARC), Indianapolis, IN, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Breier
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA. robchamb@iupui.edu.|IU Neuroscience Research Center, Indianapolis, IN, USA. robchamb@iupui.edu.|Laboratory for Translational Neuroscience of Dual Diagnosis & Development, Indiana University School of Medicine, Suite 314, 320 West 15th Street, Indianapolis, IN, 46202, USA. robchamb@iupui.edu.|Addiction Psychiatry Training Program, IU Neuroscience Research Center, Indiana University School of Medicine, Suite 314, 320 West 15th Street, Indianapolis, IN, 46202, USA. robchamb@iupui.edu.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Chambers
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016739:Behavior, Addictive / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000473:pathology; D008570:Memory, Short-Term / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016166:Free Radical Scavengers; D018722:Nicotinic Agonists; D009538:Nicotine; D003042:Cocaine; D000111:Acetylcysteine
keywords: Adolescence; Behavioral sensitization; Cocaine; Dual diagnosis; N-acetyl cysteine; Neurodevelopment; Radial arm maze; Schizophrenia