Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex

Abstract

The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic α2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity α1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that α1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while α2 and α1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in ‘focused’ vs. ‘flexible’ cognitive processes. Translationally, this information indicates that: 1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and 2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes.

Cognitive performance is associated with cerebral oxygenation and peripheral oxygen saturation, but not plasma catecholamines, during graded normobaric hypoxia

“…In addition, the performance of simple and choice reaction time type tasks is also associated with activation of the PFC, although they require considerably less neural activation (Barbas, 2000). However, the PFC is highly sensitive to its neurochemical environment and is therefore highly susceptible to stress (Arnsten, 2009 (Arnsten, 2009;Berridge & Spencer, 2016;McMorris, 2016). In addition, it is well established that glucocorticoid hormones released from the adrenal cortex during stress may also impair cognitive performance, with further evidence to suggest that noradrenaline and cortisol may have an additive effect on the decrease in central executive function (Elzinga & Roelofs, 2005).…”

Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction

“…Performance in sustained attentional focus and working memory tasks typically follows an inverted-U shaped curve of catecholamine release in the PFC, being impaired by either reduced or excessive norepinephrine and dopamine levels (Arnsten & Rubia, 2012). For example, working memory performance is reduced under conditions of low adrenergic signaling in the PFC (Berridge & Spencer, 2016), an effect replicated by blockade of α 2 receptors in the primate dlPFC (Li & Mei, 1994). Similarly, deficits in working memory are observed following pharmacological (Bubser & Schmidt, 1990; Clinton et al, 2006) or stress-induced reductions in mPFC dopamine activity (Mizoguchi et al, 2000; Novick et al, 2013), and poor performance at times when dopamine activity is low is rescued by intra-mPFC infusion of D 1 receptor agonists (Floresco & Phillips, 2001).…”

A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco‐deprived and ‐satiated smokers

“…Noradrenergic pathways in the prefrontal cortex play a critical role in supporting higher order cognitive functions (Berridge & Spencer, ). There are three classes of noradrenergic receptors, namely, α1, α2, and β receptors.…”

“…Administration of an α1 antagonist blocked any disruptive effects of stress on cognitive performance in rats, suggesting that therapeutic action at α1 may be beneficial to cognitive functioning (Birnbaum, Gobeske, Auerbach, Taylor, & Arnsten, ). Other preclinical studies have examined which aspects of cognitive performance are affected by α1 signaling, finding that activation of α1 receptors is associated with impairment of some cognitive functions (e.g., working memory) but may improve others (e.g., sustained attention; Berridge & Spencer, ).…”

“…performance are affected by α1 signaling, finding that activation of α1 receptors is associated with impairment of some cognitive functions (e.g., working memory) but may improve others (e.g., sustained attention; Berridge & Spencer, 2016).…”