Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors.

Academic Article


  • BACKGROUND: Psychostimulants improve a variety of cognitive and behavioral processes in patients with attention-deficit/hyperactivity disorder (ADHD). Limited observations suggest a potentially different dose-sensitivity of prefrontal cortex (PFC)-dependent function (narrow inverted-U-shaped dose-response curves) versus classroom/overt behavior (broad inverted U) in children with ADHD. Recent work in rodents demonstrates that methylphenidate (MPH; Ritalin) elicits a narrow inverted-U-shaped improvement in performance in PFC-dependent tests of working memory. The current studies first tested the hypothesis that PFC-dependent tasks, in general, display narrow dose sensitivity to the beneficial actions of MPH. METHODS: The effects of varying doses of MPH were examined on performance of rats in two tests of PFC-dependent cognition, sustained attention and attentional set shifting. Additionally, the effect of pretreatment with the α₁-antagonist prazosin (.5 mg/kg) on MPH-induced improvement in sustained attention was examined. RESULTS: MPH produced a broad inverted-U-shaped facilitation of sustained attention and attentional set shifting. Prior research indicates α₁-receptors impair, whereas α₂-receptors improve, working memory. In contrast, attentional set shifting is improved with α₁-receptor activation, whereas α₂-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set-shifting tasks, additional studies examined whether α₁-receptors promote sustained attention, similar to attentional set shifting. In these studies, MPH-induced improvement in sustained attention was abolished by α₁-receptor blockade. CONCLUSIONS: PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α₁- versus α₂-receptors in these processes. These observations have significant preclinical and clinical implications.
  • Authors

  • Berridge, Craig W
  • Shumsky, Jed S
  • Andrzejewski, Matt E
  • McGaughy, Jill
  • Spencer, Robert C
  • Devilbiss, David M
  • Waterhouse, Barry D
  • Status

    Publication Date

  • March 1, 2012
  • Published In


  • Adrenergic alpha-1 Receptor Antagonists
  • Animals
  • Attention
  • Central Nervous System Stimulants
  • Cognition
  • Conditioning, Operant
  • Dose-Response Relationship, Drug
  • Male
  • Methylphenidate
  • Prazosin
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, alpha-2
  • Digital Object Identifier (doi)

    Start Page

  • 467
  • End Page

  • 473
  • Volume

  • 71
  • Issue

  • 5