Genetics of childhood disorders: XIX. ADHD, Part 3: Is ADHD a noradrenergic disorder?

Dysregulation of the central noradrenergic network has long been hypothesized to underlie the pathophysiology of attentiondeficit/hyperactivity disorder (ADHD) (Arnsten et al., 1996). This hypothesis is derived largely from pharmacological data documenting that drugs which selectively modulate noradrenergic function show efficacy in treating ADHD. However, a noradrenergic hypothesis of ADHD is compelling in its own right because the noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, and vigilance. As recently reviewed by Solanto (1998), preclinical and clinical research has implicated the noradrenergic effects of stimulants in enhancing capacities such as delayed responding, working memory, and attention. Furthermore, executive function and noradrenergic activation are known to profoundly affect the performance of attention, especially the maintenance of arousal, and the ability to sustain attention on a subject, particularly a boring one. Current neuropsychological, genetic, imaging, and pharmacological data emerging in ADHD research provide compelling support for a noradrenergic hypothesis of ADHD (Arnsten et al., 1996). Attention and vigilance depend on adequate modulation by catecholamine neurotransmitters of prefrontal, cingulate, and parietal cortices, thalamus, striatum, and hippocampus. These brain networks all have a high density of catecholamine terminals. Perhaps the most compelling evidence for a noradrenergic hypothesis for ADHD derives from psychopharmacological data (Spencer et al., 1996). Preclinical studies have shown that stimulants block the reuptake of dopamine and norepinephrine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Early animal studies used 6-hydroxydopamine to lesion dopamine pathways in developing rats. Because these lesions created hyperactivity, they were thought to provide an animal model of ADHD. Although not entirely sufficient, changes in dopaminergic and noradrenGenetics of Childhood Disorders: XIX. ADHD, Part 3: Is ADHD a Noradrenergic Disorder?