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.

Figure 1

MPH exerts a broad inverted-U dose-dependent improvement in performance in a sustained attention test. Panel A: Shown are the effects of varying doses of MPH on performance in a signal detection test of sustained attention as measured by change in d′ from baseline performance (Madison, WI testing; Triangles, left axis). Relative to vehicle treatment (Veh) 0.5 mg/kg MPH significantly improved performance, consistent with our previous observations (4). 2.0 mg/kg MPH produced an even larger improvement in performance in this task while 4.0 mg/kg MPH did not improve and 8.0 mg/kg MPH significantly impaired performance. The breadth of this dose response curve differs from that seen in a delayed response task of spatial working memory (Squares, right axis; data from 10). For working memory testing, animals were required to alternate arm entries following a delay (10–120 seconds) that yielded 70–80% accurate performance. MPH produces a substantially narrower inverted-U shaped facilitation of working memory performance than seen in the sustained attention task, with maximal improvement occurring at 0.5 mg/kg and impairment at 2.0 mg/kg. Panel B: Effects of varying doses of MPH on sustained attention as tested in Philadelphia, PA. Despite significant differences in testing procedures and baseline levels of performance (see Methods and Results) nearly identical dose-response effects of MPH on sustained attention were obtained to those shown in Panel A, with maximal improvement in performance occurring at 2.0 mg/kg. In particular, the magnitude of the increase in d′ seen with this dose of MPH was nearly identical across the two laboratories. ^*P < 0.05; ^**P < 0.01 relative to vehicle treatment.

Figure 2

Dose-dependent improvement in attentional set shifting by MPH is similar to that seen in sustained attention testing. Shown are the effects of varying doses of MPH (0.5 mg/kg, 2.0 mg/kg and 4.0 mg/kg) on intradimensional (IDS) and extradimensional (EDS) tests. As shown in the top panel, MPH significantly improved EDS as indicated by the reduction in the number of trials needed to reach criterion performance on this test of attentional set shifting. Similar to that seen in the sustained attention task, maximal facilitation (as indicated by the number of trials to reach criterion) was observed at 2.0 mg/kg (IP), but not 4.0 mg/kg. There was no effect of the drug on the formation of the attentional set (bottom graph). ^*P < 0.05; ^**P < 0.01 relative to vehicle treatment.

Figure 3

α₁-receptor blockade prevents MPH-induced improvement in sustained attention. Animals were treated with either: 1) 2.0 mg/kg MPH; 2) 0.5 mg/kg of the α₁-receptor antagonist, prazosin; 3) 0.5 mg/kg prazosin + 2.0 mg/kg MPH. Shown are values for d′, expressed as a change from baseline. 2.0 mg/kg MPH improved performance in this task, similar to that seen in Figure 1. Treatment with prazosin had no effect on sustained attention performance. In contrast, this dose of prazosin completely blocked the facilitating effects of MPH on sustained attention. ^**P < 0.01 vs. baseline; ⁺P < 0.05 vs. vehicle.