Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex

Psychopharmacology (Berl). 2008 Sep;200(1):39-50. doi: 10.1007/s00213-008-1097-8. Epub 2008 Jun 22.

Abstract

Background: The majority of studies assessing executive function in attention deficit disorder (ADD) have shown deficits in attentional set shifting using either the Wisconsin card sorting task or the intra-dimensional/extra-dimensional set-shifting task (ID/ED). Damage to the prefrontal cortex in humans, primates, and rodents impairs extra-dimensional (ED) shifts. Noradrenergic depletion of the medial prefrontal cortex in rats is sufficient to impair attentional set shifting. Atomoxetine, a selective norepinephrine (NE) re-uptake inhibitor, is hypothesized to produce beneficial effects in patient with ADD by augmenting NE release in prefrontal cortex.

Materials and methods: We assessed the effects of systemic administration of atomoxetine (0.0, 0.1, 0.3, and 0.9 mg/kg/ml) in normal and noradrenergically lesioned (NE-LX) rats on attentional-set shifts. We replicated findings showing NE-LX rats are selectively impaired on the ED shifts but not reversals or other discriminations.

Results: Atomoxetine remediated the attentional set-shifting impairments in NE-LX rats but impaired ED performance of non-lesioned rats.

Discussion: Though atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.

MeSH terms

  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / pharmacology*
  • Animals
  • Atomoxetine Hydrochloride
  • Attention / drug effects
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Behavior, Animal / drug effects
  • Discrimination Learning / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Norepinephrine / metabolism
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Propylamines / administration & dosage
  • Propylamines / pharmacology*
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Long-Evans

Substances

  • Adrenergic Uptake Inhibitors
  • Propylamines
  • Atomoxetine Hydrochloride
  • Norepinephrine