Functional Roles of Norepinephrine and Dopamine in ADHD

Robert D. Hunt, MD Medscape Psychiatry & Mental Health. 2006;11(1) 2006 Medscape Posted 03/09/2006

Introduction
While norepinephrine (NE) and dopamine (DA) are certainly not the only neurotransmitters involved in ADHD, there is considerable evidence that these neurotransmitters play essential roles in attention and thinking. It may be an artifact to attempt to attribute unique functions to each neurotransmitter since they collaborate in facilitating many cognitive and affective functions. Both agents contribute to maintaining alertness, increasing focus, and sustaining thought, effort, and motivation. NE and DA are structurally very similar, differing only in the presence of a hydroxyl group; DA is a precursor to NE synthesis in the brain. However, distinctions in their sources of origin and their projections in the brain and differences in the behavioral effect of selective alternations suggest that these neurotransmitters have discrete complementary roles in the brain. Although these neurotransmitters affect related components of attention, they activate distinct receptors including specific subtypes of NE and DA, usually identified as D1, D2, and D3 receptors, etc.[1] Arising from the locus coeruleus (LC), a small area in the basal brain located near the pons, are the cell bodies from which NE is generated. From this region, they project widely and diffusely in the brain. The broad dispersion of NE itself suggests a broad role for NE as a "neuromodulator," a term contributed by Floyd Bloom, the pioneer of functional research on NE. The concept of a neuromodulator suggests a more generalized impact of NE on tonic and phasic arousal than might be mediated by a more discretely localized neurotransmitter. [2]

NE Function
NE has an emerging role in several essential processes: (1) maintaining and increasing overall arousal, (2) contributing to affect regulation related to excitability and response to danger or opportunity, and (3) contributing to memory storage and retrieval, especially affect-related or emotionally intense events. While NE has a critical role in emergency response, it also assists in maintaining basal or tonic alertness. At a quieter moment, reading a book, studying at night, the effort to remain alert and stay on task partially mediated by NE. [3] The functional role of NE might be illustrated by imagining the experience of walking alone in the woods. As the sun begins to set, you suddenly hear an abrupt crack, the sound of a stick being broken by an unseen object moving several yards away. Immediately your senses burst alive -your head turns in the direction of the sound, your heart begins to race as you seek to determine the origin of the noise. Your thoughts quickly seek to discern the object and determine, Is this opportunity or danger? Is this going to eat me or am I going to eat it? The physical effect of increased pulse rate and sweating primarily reflects a burst of epinephrine arising predominately from the adrenal glands. But the cognitive, mental component of alerting is mediated by centrally acting NE arising from the LC. This rapid burst of cortical arousal enhances alertness that facilitates discrimination and activates executive function or reasoning. "The sound was too far away to be a small animal, not a badger or fox. It could be a wolf." Reasoning is triggered: Should I run, freeze or wait? Do I drop to the ground, or stand perfectly still?

Through modulation of wide cortical network, NE activates electrophysiologic and behavioral responses essential to the processing of relevance or salience of information at 2 basic levels of action. At a tonic level, NE contributes to the initiation and maintenance of behavioral and forebrain neuronal activity essential for the collection and processing of sensory information. Second, NE responds phasicly to modulate the salience of sensory information through diverse concentration-dependent activity in cortical and subcortical regions essential for attention and energy.[4] NE modulation appears to be altered by experience. The long-term neuronal function and behavioral response are synaptically mediated, though genetically encoded. However, the sensitivity of noradrenergic response is altered by prior experience and behaviors that impact the sensitivity of this NE neurotransmitter system. The ability of a given stimulus to increase LC discharge appears independent of its affective valence, either appetitive or aversive. [3] Thus, the LC-NE system is critical to neuronal interaction with and navigation of sensorial experience. Alteration of this LC-NA system disrupts cognitive and arousal function that constitutes a component of the symptoms of multiple disorders, including ADHD. This also includes such domains as basal and response activity, and overall, all levels of cognitive alertness essential for processing stimuli and sustaining attention and thought. [4] NE activation also affects other disorders impacted by arousal, such as the activity and sleep component of affective disorders, or anxiety-intensity in posttraumatic stress disorder. Pharmacologic treatment targeting NE symptoms of initiation, arousal, or memory dysfunction appears useful in treating the spectrum of symptoms in ADHD. Projections into the limbic system and to frontal B1 and alpha-2a receptors have an essential role in differentiation of focused attention vs inhibition of distractions while paying attention. [5] The catecholamine hypothesis of ADHD has reflected measures of NE, epinephrine, and DA in ADHD and normals, which must be understood in the context of neuroimaging and animal studies. A role for all 3 neurotransmitters exists in ADHD. These neurotransmitters affect attention, alertness, and arousal through a crucial balance essential for maintaining homeostasis and responding to acute demand. A hypothesis suggesting "too much" or "too little" of a single neurotransmitter does not explain the diversity or complexity of ADHD symptoms. Ultimately, no neurobiological process as complex as attention is likely to be modulated by one neurotransmitter system.[1] NE contributes to the regulation of both tonic and phasic arousal, related to generalized alertness and to acute activation, such as a startle response to an abrupt change in the environment. NE is also critical to executive functioning involved in reasoning, learning, and problem solving.[6] Attention is a multicomponent process that links striatal filtering of internally processed stimuli and motivation, selective projection to the prefrontal cortex, and interaction with a posterior system for processing sensory information. The dysregulation of central nervous system NE in ADHD decreases the efficiency of this system so that it does not efficiently "prime" or activate the cortical posterior attention system to external stimuli. Effective mental processing of information involves an anterior "executive" attention system that may also depend on dopaminergic input. The peripheral epinephrine system may be a critical factor in the response of individuals with ADHD to stimulant medication.[1] Measures of Catecholamines: Conflicting Results Differences in catecholamines have been examined in relation to comorbidities and to performance on cognitive tasks. Shekim and associates[7] found only subtle differences in psychoeducational test performance in relation to specific levels of homovanyllic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Urinary noradrenergic activity (EP and NE) of a group of boys with ADHD measured during classroom tasks suggested decreased sympathetic and

adrenomedullary function as evidenced by substantially lower urinary epinephrine excretion observed in the ADHD inactivated subtype compared with the controls. [8] Presynaptic inhibitory alpha-adrenergic receptors are involved in regulating the release of NE through a negative feedback mechanism mediated by NE. Increased alpha2-adrenergic receptor activity suggests diminished NE release and activity. Conversely, decreased alpha2-adrenergic activity may reflect an increase in NE functioning. Evidence suggesting the involvement of a disturbance in NE activity in the pathophysiology of ADHD in childhood includes the finding that 23 ADHD boys tended to have lower levels of alpha2-receptor binding in platelets than did controls.[9] The administration of d-amphetamine did not have any effect on alpha2-receptor binding in ADHD boys. Those who did not demonstrate improvement from d-amphetamine treatment had the lowest alpha2-receptor binding compared with both responders and controls. These findings suggest a normal alpha2-adrenergic activity in ADHD boys who respond to damphetamine, in contrast to a possible increase in NE release in ADHD boys who are amphetamine nonresponders, perhaps secondary to decreased alpha2-adrenergic receptors. [10,11]

Comorbidities
Anxiety. ADHD children who also had anxiety disorder were found to have increased excretion of the major extracellular NE metabolite, normetanephrine. This suggested that children with ADHD may have a higher tonic activity of the NE system than do controls. Elevated NE levels might be expected to correlate with enhanced baseline activity as well as with increased anxiety. Higher levels of noradrenergic arousal may actually drive symptoms of increased activity, and may overwhelm cognitive filtering and inhibitory processes. This heightened arousal could lead to symptoms of behavioral hyperactivity, enhanced emotional reactivity, as well as diminished selective and sustained attention.[12] Dyslexia. The relation of noradrenergic function to reading difficulties in ADHD children was studied by Halperin and colleagues.[13] They found that plasma levels of the NA metabolite MHPG were significantly lower when measured during performance of cognitive tasks in ADHD children without reading difficulties than in those with reading difficulties. Plasma MHPG was inversely associated with measures of academic achievement and verbal processing but did not correlate with teacher ratings of behavior or with performance on a continuous performance test. Thus, children with ADHD are not homogenous with regard to NA functioning, which may reflect the presence of other cognitive or learning deficits. Physical Activation. Another index of catecholamine functioning in ADHD is the response to physical activation from exercise that is known to boost noradrenergic activity. Wigal and associates[14] compared the noradrenergic response to equivalent exercise in treatment-naive ADHD boys and age-matched normal controls. Immediately after exercise, epinephrine and NE were increased regardless of diagnosis, but the responses were substantially blunted in the ADHD group (P = .018). However, circulating DA was differentially affected: DA increased in controls, but not in ADHD subjects, suggesting a decrease in dopaminergic response in ADHD. In addition, a significant attenuation in lactate response to exercise was found in ADHD between groups (P < .005). These data suggest that catecholamine excretion after exercise is increased in controls, but not in ADHD. Differences in neurotransmitter levels may reflect the degree of activity rather the specific underlying psychiatric diagnosis. When Hanna and colleagues [15] measured multiple urinary catecholamines, they found a trend for lower urinary epinephrine and DOPEG levels in hyperactive boys. Catecholamine response in ADHD children was blunted after ingestion of glucose.[16] The relationship of blood levels of desipramine to clinical response and neurotransmitter effect was assessed by Donnelly and colleagues at the National Institutes of Health.[17]

The relationship of monoamine metabolites in the cerebrospinal fluid (CSF), plasma, and urine was determined for 29 prepubertal boys, aged 6-12, with ADHD. [18] Levels of CSF 5hydroxyindoleacetic acid (5-HIAA), HVA, and MHPG, the metabolites of serotonin, DA, and NE, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity, but in the unexpected direction. CSF 5-HIAA correlated positively with a history of prior aggression; HVA in CSF was positively correlated with several measures of hyperactivity. Collectively, these studies suggest that ADHD itself is correlated with higher baseline noradrenergic activation when measured by urinary excretion of NE, epinephrine, and normetanephrine. However, plasma levels of the NE metabolite MHPG were lower in ADHD children without reading difficulties. NE is considered to be a mediator of executive function including problem solving, priority setting, and selective attention. In addition, NE may assist in multiple aspects of visual word decoding and in interpretation of reading that requires new learning or applied problem solving. NE has a clear role in executive function including priority setting, problem solving, and intentional behavior and organizational thought. [3] Given the essential role of NE in modulating arousal and sensory sensitivity and cortical processing of analysis and reasoning, it is understandable that noradrenergic effects of psychostimulants, especially amphetamines, and of atomoxetine may constitute an important component of effective treatment of ADHD. In addition, changes in alpha2-adrenoceptors impair working memory performance and eliminate the cognitive enhancement usually facilitated by guanfacine.[5]

Dopamine in ADHD
DA pathways in the brain arise primarily from the ventral tegmentum and have multiple cortical projections through pathways involved in conscious and intentional control of movement and in brain regions that mediate emotion and sensitivity to rewards. The reward pathway is predominantly based in the nucleus accumbens. This connection is related to interest that is highly integrated with attention. ADHD individuals typically describe that they can pay attention to topics or information that interest them, but have great difficulty sustaining focus on important information that is not intrinsically interesting. The DA projections to the mesocortex are relevant to the ability to attach attention and to relate attention to working memory and problem solving. DA projections to mesocortical areas mediate prefrontal cortical processes that enable active suppression of distractions and inhibit inappropriate behavioral expressions of tangential thoughts, ideas, or behaviors. Many ADHD individuals appear unable to inhibit or delay reacting -even when their response might have dire consequences. They cannot remain quiet; they blurt out thoughts and ideas independent of their social or cognitive relevance. In parallel to their high level of motor restlessness, they often describe themselves as having "wiggly minds" or "grasshopper thoughts" that jump from one topic to another. The inhibition of excessive fidgetiness and functionally random thoughts are among the most beneficial effects of psychostimulant treatment. The mesodorsal-lateral DA projections are more involved in working memory -- the ability to hold an idea in conscious awareness and analyze it thoroughly before making decisions. The capacity for executive function involved in reasoning, planning, and problem solving necessitates a sustained working memory that requires activation of these dorsolateral projections to DRD2 receptors. Thus, these dopaminergic areas are engaged in attention to detail and increase perseveration of thinking -- the ability to sustain working memory. This pathway, when overly activated, may decrease cognitive flexibility and enhance perseveration of thought while decreasing cognitive flexibility in seeking alternative solutions or responses to a problem or situation. By contrast, the meso-orbital DA projections impact the ability to make thoughtful interpersonal decisions and to inhibit excessive reactivity or impulsive social responding. This inhibitory control extends to social functioning related to the ability to inhibit overreacting, blurting out, and impulsive responding.

This pattern of impulsive behavior, excessive talking, and emotional lability can be a manifestation of deficits in meso-orbital DA pathways. In addition, it is corrected by psychostimulants that diminish not only overactivity, but irritability and impulsivity that often underlie the social and interpersonal difficulties experienced by ADHD individuals. Catecholamines not only facilitate attention, they are essential to executive function. The prefrontal cortex directs behaviors, thoughts, and feelings represented in working memory. This representational knowledge is essential to fundamental cognitive abilities that compromise executive functions. These encompass the ability to (1) inhibit inappropriate behaviors and thoughts, (2) regulate our attention, (3) monitor our actions, and (4) plan and organize for the future. Difficulties with these prefrontal cortex functions are evident in neuropsychological and imaging studies of ADHD patients and account for many of the common behavioral symptoms. Measures of prefrontal cortical functioning in animals indicate that these functions are sensitive to small changes in catecholamine modulation of prefrontal cortex cells that can produce profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of NE acting at postsynaptic alpha2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine alpha2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of ADHD, including impulsivity and locomotor hyperactivity. Conversely, stimulation of prefrontal cortical alpha2adrenoceptors strengthens prefrontal cortex regulation of behavior and reduces distractibility. Thus, effective treatments for ADHD facilitate catecholamine transmission and apparently have their therapeutic actions by optimizing catecholamine actions in the prefrontal cortex. [19] Measures of DA in ADHD In some of the previous studies, DA and its metabolite HVA were measured concurrently with NE. In their study of urinary catecholamines, Shekim and colleagues [20] found that the ADHD boys who responded to d-amphetamine treatment, including those with normal MHPG, excreted lower amounts of HVA than control boys. Conversely, those with normal HVA excreted low amounts of MHPG; d-amphetamine decreased HVA in drug responders who exhibited normal HVA levels at baseline. Castellanos and associates[18] found that HVA in CSF was positively correlated with several measures of hyperactivity and with behavioral measures of aggression. Collectively, studies of catecholamines suggest that ADHD symptoms are not the prerogative of an alternation in a single neurotransmitter system, but may reflect the relative functioning of both NE and DA systems. Further, the impact of psychostimulant treatment on catecholamines may depend on their baseline pretreatment levels. Wigal and associates[14] found that exercise increased DA excretion in controls, but not in ADHD subjects, suggesting a decrease in dopaminergic response in ADHD. These data suggest that catecholamine excretion after exercise is increased in controls, but not in ADHD patients. Treatment Implications The implications of these underlying catecholaminergic mechanisms for treatment of ADHD/ADD suggest that medications that increase catecholamines may fasciculate attention. [21] The major effect of methylphenidate is to increase synaptic concentration of dopamine by blocking presynaptic DA reuptake. Amphetamines also block DA reuptake but have 2 additional effects of increased production of both DA and NE.[22] While both medications increase attention, the noradrenergic effects of amphetamine may contribute to increased energy and enhanced executive function. DA may be more essential to attaching attention; NE may contribute more to executive function. Atomoxetine, through acting primarily on NE, has secondary effects of increasing prefrontal cortical DA. Modafinil may enhance attention predominantly by increasing arousal and alertness in patients with low-energy ADHD.[23,24]

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Supported by an independent educational grant from Shire.

Robert D. Hunt, MD, Associate Clinical Professor of Psychiatry, Vanderbilt University Medical School, Nashville, Tennessee; CEO & Medical Director, Center for Attention and Brain Function, Nashville, Tennessee Disclosure: Robert D. Hunt, MD, has disclosed that he has received grants for clinical research from Lilly, and has served as an advisor or consultant to Shire, Cephalon, Novartis, and AstraZeneca.