Accepted for publication (PostPrint)
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.
Berridge, Craig; Shumsky, Jed; Andrzejewski, Matt; McGaughy, Jill; Spencer, Robert; Devilbiss, David; and Waterhouse, Barry, "Differential Sensitivity to Psychostimulants Across Prefrontal Cognitive Tasks: Differential Involvement of Noradrenergic α1- and α2-Receptors" (2012). School of Osteopathic Medicine Faculty Scholarship. 45.
Berridge CW, Shumsky JS, Andrzejewski ME, McGaughy JA, Spencer RC, Devilbiss DM, Waterhouse BD. Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors. Biol Psychiatry. 2012 Mar 1;71(5):467-73. Epub 2011 Sep 3. doi: 10.1016/j.biopsych.2011.07.022. PMID: 21890109. PMCID: PMC3233638.