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

Abstract

Background Psychostimulants improve a variety of cognitive/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) vs. classroom/overt behavior (broad inverted-U) in children with ADHD. Recent work in rodents observed 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 (0.5 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, while α2-receptors improve, working memory. In contrast, attentional set shifting is improved with α1-receptor activation, while 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- vs. α2-receptors in these processes. These observations have significant preclinical and clinical implications.

Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices

“…Many studies have provided evidence of a facilitating effect of NE or LC activation on the signal-processing capabilities of various networks in the mammalian brain, but the extent to which such actions are uniform and simultaneous across forebrain terminal fields has not been resolved. Heterogeneity among LC-prefrontal projection neurons opens the door for differential actions of LC output on specified prefrontal subregions as has been suggested by selective lesion and pharmacologic studies (9,10,30,38,39). Recent work using similar experimental strategies has revealed similar novel functional and organizational principles of dopamine projections to prefrontal versus limbic terminal fields (33), thus providing considerable new insights regarding the impact of dopaminergic inputs to those circuitries in health and disease.…”

Animal model of methylphenidate's long-term memory-enhancing effects

“…MPH's clinical efficacy is generally modeled using attention or cognitive control tasks, such as attentional set-shift, stopsignal, and five-choice serial reaction time (Puumala et al 1996;Robbins 2002;Arnsten and Dudley 2005;Eagle et al 2007;Berridge et al 2012;Humby et al 2013). However, these models do not assess LTM and are difficult to implement in high throughput drug development as they are complex, sometimes require extensive training, and often are in monkeys.…”

Persistent α1-adrenergic receptor function in the nucleus locus coeruleus causes hyperexcitability in AD/HD model rats

“…High levels of noradrenaline release can impair cognitive function through ␣ 1 -AR activation (Arnsten and Pliszka 2011;Arnsten et al 2007;Birnbaum et al 1999). By contrast, ␣ 1 -AR activation is necessary for MPH-induced improvement in sustained attention (Berridge et al 2012). Low-dose MPH increases NA in the prefrontal cortex and improves cognitive function Devilbiss and Berridge 2006).…”

“…Although the noradrenergic receptor has three subtypes (␣ 1 , ␣ 2 and ␤), in the present study we only focused on the ␣ 1 -and ␣ 2 -ARs in LC neurons. The noradrenergic ␣ 1 -ARs exist primarily at postsynaptic sites, whereas ␣ 2 -ARs exist at both pre-and postsynaptic sites (Berridge and Waterhouse 2003). Noradrenergic signals are thought to be inhibited by an autoreceptor via an axon-recurrent collateral.…”