Differential Sensitivity to Psychostimulants Across Prefrontal Cognitive Tasks: Differential Involvement of Noradrenergic α1- and α2-Receptors

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 alpha(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 alpha(1)-receptors impair, whereas alpha(2)-receptors improve, working memory. In contrast, attentional set shifting is improved with alpha(1)-receptor activation, whereas alpha(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 alpha(1)-receptors promote sustained attention, similar to attentional set shifting. In these studies, MPH-induced improvement in sustained attention was abolished by alpha(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 alpha(1)- versus alpha(2)-receptors in these processes. These observations have significant preclinical and clinical implications.