title: Differential roles for cortical versus sub-cortical noradrenaline and modulation of impulsivity in the rat.
abstract: Atomoxetine is a noradrenaline re-uptake inhibitor licensed for the treatment of adult and childhood attention deficit hyperactivity disorder. Although atomoxetine has established efficacy, the mechanisms which mediate its effects are not well understood.
  
  
  
  In this study, we investigated the role of cortical versus sub-cortical noradrenaline by using focal dopamine beta hydroxylase-saporin-induced lesions, to the prefrontal cortex (n = 16) or nucleus accumbens shell (n = 18).
  
  
  
  Healthy animals were tested by using the forced-choice serial reaction time task to assess the impact of the lesion on baseline performance and the response to atomoxetine and the psychostimulant amphetamine.
  
  
  
  We observed attenuation in the efficacy of atomoxetine in animals with lesions to the nucleus accumbens shell, but not the prefrontal cortex. Amphetamine-induced increases in premature responses were potentiated in animals with lesions to the prefrontal cortex, but not the nucleus accumbens shell.
  
  
  
  These data suggest that noradrenaline in the nucleus accumbens shell plays an important role in the effects of atomoxetine. Under these conditions, prefrontal cortex noradrenaline did not appear to contribute to atomoxetine's effects suggesting a lack of cortical-mediated "top-down" modulation. Noradrenaline in the prefrontal cortex appears to contribute to the modulation of impulsive responding in amphetamine-treated animals, with a loss of noradrenaline associated with potentiation of its effects. These data demonstrate a potential dissociation between cortical and sub-cortical noradrenergic mechanisms and impulse control in terms of the actions of atomoxetine and amphetamine.
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Benn
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK. Emma.S.J.Robinson@bristol.ac.uk.
authors.forename: Emma S J
authors.initials: ES
authors.lastname: Robinson
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D011437:Propylamines / Q000494:pharmacology; D051381:Rats
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine
keywords: Amphetamine; Atomoxetine; Impulse control; Noradrenaline; Nucleus accumbens; Prefrontal cortex