Functional Roles of Norepinephrine and Dopamine in ADHD

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]

1. Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry. 1996;35:264-272. Abstract

2. Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology, Eighth Edition. New York, NY: Oxford University Press; 2003.

3. Berridge CW, Waterhouse BD. The locus coeruleus -noradrenergic system: modulation of behavioral state and state-dependent cognitive processes [review]. Brain Res Brain Res Rev. 2003;42:33-84. Abstract

4. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility [review]. Biol Psychiatry. 1999;46:1309-1320. Abstract

5. Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF. Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci. 2002;22:8771-8777. Abstract

6. Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder [review]. Biol Psychiatry. 1999;46:1234-1242. Abstract

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