title: Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors.
abstract: 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: Department of Psychology, University of Wisconsin, Madison, Wisconsin 53706, USA. berridge@wisc.edu
authors: Craig W
authors: CW
authors: Berridge
authors: Jed S
authors: JS
authors: Shumsky
authors: Matt E
authors: ME
authors: Andrzejewski
authors: Jill A
authors: JA
authors: McGaughy
authors: Robert C
authors: RC
authors: Spencer
authors: David M
authors: DM
authors: Devilbiss
authors: Barry D
authors: BD
authors: Waterhouse
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000697:Central Nervous System Stimulants; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D008774:Methylphenidate; D011224:Prazosin