Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders

The primary symptoms of attention deficit/hyperactivity disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the “top-down” regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α2A-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α2A-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α2A-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.

Research Highlights
► Catecholamines have a large effect on prefrontal cortical functions.
► Dopamine and norepinephrine both have inverted-U actions.
► Norepinephrine strengthens prefrontal connections via post-synaptic alpha2A-receptors.
► Dopamine sculpts network connections through D1 receptors.
► Medications for ADHD optimize or mimic these catecholamine actions.