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

Abstract

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 α(2A)-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α(2A)-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-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.

Figure 1

The PFC regulates attention, behavior, and emotion through extensive network connections with other brain regions. Networks of neurons within the PFC (insert) excite each other to maintain representations of goals and rules used to guide attention, behavior, and emotion.

Figure 2

The PFC is very sensitive to its neurochemical environment; both insufficient and excessive catecholamine release impair PFC function. The catecholamines norepinephrine (NE) and dopamine (DA) are released in the PFC according to arousal state: very little during fatigue (and boredom?), a moderate amount of phasic release to relevant stimuli during alert, nonstressed waking, and high tonic release under stressful conditions. Moderate levels of NE engage postsynaptic α_2A-receptors to improve PFC function, while higher levels engage α₁- and β-receptors, which impair PFC function. Thus, optimal regulation of PFC function depends on postsynaptic α_2A- and moderate D1-receptor stimulation. Animal studies suggest that therapeutic doses of stimulants improve PFC function by increasing endogenous noradrenergic and dopaminergic stimulation of α_2A- and D1-receptors, respectively. ADHD = attention-deficit/hyperactivity disorder.

Figure 3

Stimulation of post-synaptic, α_2A-receptors on PFC neurons by norepinephrine (NE) or guanfacine strengthens the functional connections between prefrontal cortex (PFC) neurons. Many α_2A-receptors are found on the dendritic spines where PFC neurons form network connections. Top row: When there is no α_2A-receptor stimulation, cyclic adenosine monophosphate (cAMP) levels are high, potassium channels open, weakening nearby synaptic inputs. As a result, PFC network firing decreases, and there is weakened capability to regulate attention, behavior, or emotion. Bottom row: When α_2A-receptors are stimulated by NE or by guanfacine, they close nearby potassium channels, increasing the efficacy of network inputs, and facilitating PFC function.