TY - JOUR
T1 - Differential sensitivity to psychostimulants across prefrontal cognitive tasks
T2 - Differential involvement of noradrenergic α 1- and α 2-receptors
AU - Berridge, Craig W.
AU - Shumsky, Jed S.
AU - Andrzejewski, Matt E.
AU - McGaughy, Jill A.
AU - Spencer, Robert C.
AU - Devilbiss, David M.
AU - Waterhouse, Barry D.
N1 - Funding Information:
This work was supported by PHS Grant Nos. MH081843 , DA000389 , DA017960 , MH087921 , the National Science Foundation (Grant No. NSF 0918555 ), the Wisconsin Institutes of Discovery, and the University of Wisconsin Graduate School and PA Tobacco Formula Funds.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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 doseresponse 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 α 1-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 α 1-receptors impair, whereas α 2-receptors improve, working memory. In contrast, attentional set shifting is improved with α 1-receptor activation, whereas α 2-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set-shifting tasks, additional studies examined whether α 1- receptors promote sustained attention, similar to attentional set shifting. In these studies, MPH-induced improvement in sustained attention was abolished by α 1-receptor blockade. Conclusions: PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α 1- versus α 2-receptors in these processes. These observations have significant preclinical and clinical implications.
AB - 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 doseresponse 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 α 1-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 α 1-receptors impair, whereas α 2-receptors improve, working memory. In contrast, attentional set shifting is improved with α 1-receptor activation, whereas α 2-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set-shifting tasks, additional studies examined whether α 1- receptors promote sustained attention, similar to attentional set shifting. In these studies, MPH-induced improvement in sustained attention was abolished by α 1-receptor blockade. Conclusions: PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α 1- versus α 2-receptors in these processes. These observations have significant preclinical and clinical implications.
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U2 - 10.1016/j.biopsych.2011.07.022
DO - 10.1016/j.biopsych.2011.07.022
M3 - Article
C2 - 21890109
AN - SCOPUS:84858751083
SN - 0006-3223
VL - 71
SP - 467
EP - 473
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 5
ER -