title: Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex.
abstract: BACKGROUND
  Impulsivity is a key symptom of attention-deficit hyperactivity disorder (ADHD). The use of the norepinephrine reuptake inhibitor, atomoxetine, to treat ADHD suggests that the activity of the norepinephrine transporter (NET) may be important in regulating impulsive behavior. Many ADHD patients receive chronic drug treatment during adolescence, a time when frontal brain regions important for impulse control are undergoing extensive development.
  
  
  OBJECTIVE
  The current study aimed to determine the effects of chronic atomoxetine treatment during adolescence in rats on two distinct forms of impulsivity in adulthood and whether any behavioral changes were accompanied by alterations in mRNA or protein levels within the frontal cortices.
  
  
  METHODS
  Rats received daily injections of saline or atomoxetine (1 mg/kg) during adolescence (postnatal days 40-54). Two weeks later, animals were trained to perform either the delay-discounting test or the five-choice serial reaction time task (5CSRT).
  
  
  RESULTS
  Adolescent atomoxetine treatment caused a stable decrease in selection of small immediate rewards over larger delayed rewards (impulsive choice) in adulthood, but did not affect premature responding (impulsive action) in the 5CSRT. Chronic atomoxetine treatment also altered the ability of acute atomoxetine to modulate aspects of impulsivity, but did not change the response to d-amphetamine. Ex vivo analysis of brain tissue indicated that chronic atomoxetine decreased phosphorylation of CREB and ERK in the orbitofrontal cortex and decreased mRNA for BDNF and cdk5.
  
  
  CONCLUSIONS
  These data suggest that repeated administration of atomoxetine in adolescence can lead to stable decreases in impulsive choice during adulthood, potentially via modulating development of the orbitofrontal cortex.
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, V6T 1Z4, Canada.
authors.forename: Haosheng
authors.initials: H
authors.lastname: Sun
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cocker
authors.forename: Fiona D
authors.initials: FD
authors.lastname: Zeeb
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Winstanley
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis; D003913:Dextroamphetamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056726:Genetic Association Studies / Q000379:methods / Q000706:statistics & numerical data; D007175:Impulsive Behavior / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D003913:Dextroamphetamine