Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control

Abstract

Rationale Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α2 adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established. Objectives This study tested the effect of the postsynaptic α2 adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex. Methods Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, crossover design. Results Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces, but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions. Conclusions These results provide evidence that guanfacine stimulation of postsynaptic α2 adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α2 adrenoceptor agonist treatment of attention-deficit hyperactivity disorder (ADHD).

Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: A randomized, controlled, Phase III trial

“…However, through its specific mechanism of action, it has shown several of the same side effects as stimulants, such as increased heart rate and blood pressure (Bushe and Savill, 2014), and up to 12 weeks of treatment can be necessary before a full response is demonstrated (Bangs et al, 2008;Bushe and Savill, 2014). Although the precise underlying physiological mechanisms of GXR are unknown, the beneficial behavioral effect of GXR on pre-frontal cortex cognitive functions has been well documented (Malhotra et al, 2006;Schulz et al, 2013;Singh-Curry et al, 2011;Wang et al, 2007). Efficacy and safety of GXR in patients with ADHD are well established (Biederman et al, 2008b;Connor et al, 2010;Kollins et al, 2011;Newcorn et al, 2013;Sallee et al, 2009b).…”

Emotion Dysregulation in Attention Deficit Hyperactivity Disorder

“…Postsynaptic alpha-2 adrenoceptor agonists such as guanfacine treat core symptoms of ADHD and oppositionality (129). In healthy adults, guanfacine reverses the bias to respond less accurately to negative compared to positive emotional stimuli, partly through boosting activation of the left dorsolateral prefrontal cortex (130). Given the interactions between the lateral prefrontal cortex and the ventral/medial prefrontal cortical regions linked to emotion regulation, guanfacine emerges as a potential 'emotion regulator' in ADHD.…”

A Review of the Rationale and Clinical Utilization of α2-Adrenoceptor Agonists for the Treatment of Attention-Deficit/Hyperactivity and Related Disorders

“…Given the cognitive actions of a 2 -adrenoceptor agonists to modify attentional orientation and promote adaptation to environmental demands, there is currently ongoing research to examine the mechanisms by which these agents impact functioning of specific brain regions within circuits subserving attention and selfregulation, including emotion regulation (Schulz et al 2013). Recent reviews (Sara 2009;Brady et al 2011) and one open-label study of children with symptoms of traumatic stress (Connor et al 2013) have suggested that cognitive enhancement via a 2 -adrenoceptor agonists might be beneficial in conditions other than ADHD (e.g., posttraumatic stress disorder and substance use disorder).…”