Norepinephrine

In the body (peripherally), adrenaline and norepinephrine function as hormones that are continuously produced and metabolized. Adrenaline is produced mainly in the adrenal medulla and helps the body respond to stress. Norepinephrine (NE) is generated primarily in sympathetic nerve endings. Adrenaline and norepinephrine promote oxygen utilization and stimulate fat breakdown.

In the brain, norepinephrine acts as a neurotransmitter. In addition to its long-recognized influence on arousal, wakefulness, and the perception of sensory signals, it also plays a role in behavior and cognition, such as memory, learning, attention, vigilance, mood, and motivation.¹²
Norepinephrine affects the reticular activating system and impulse control. The release of norepinephrine in the brain is influenced, for example, by stress or sleep. Norepinephrine levels can be increased by mental or physical activity.

Norepinephrine (like all monoamines) is primarily a volume transmitter. Volume transmission acts like a volume control, amplifying or inhibiting other areas of the brain without directly influencing (synaptic) information processing.³ Norepinephrine specifically influences the signal-to-noise ratio ( which signals are salient = noticeable), while dopamine influences signal strength (which signals are relevant) and serotonin shifts global network dynamics (e.g., impulsive vs. stable, exploratory vs. conservative). To use a musical analogy, monoamines act as “volume transmitters” that control the volume of entire sections of the orchestra (all violins, all trumpets), while synaptic transmission influences the notes played by individual instruments.
In addition to its role in volume transmission, norepinephrine is also involved, to a lesser extent, in information processing as a synaptic neurotransmitter.

In ADHD, norepinephrine has the second-greatest influence after dopamine. It plays a role in the brain’s attention centers and affects motivation, mood, and memory. It is believed that ADHD is associated with delayed brain maturation, which is accompanied by increased norepinephrine activity in the brain. The levels of norepinephrine metabolites in urine normalize with age.
Like dopamine, norepinephrine is also a neurotrophic factor, meaning it influences brain development and neuroplasticity.

There are various types of noradrenergic receptors, known as adrenoceptors: α1, α2, and β receptors. These receptors can be activated by agonists or blocked by antagonists. Norepinephrine also binds to some dopamine receptors, just as dopamine binds to some adrenoceptors.

1. Adrenaline and Norepinephrine in the Body (Hormones)¶

For an overview of this, see Hässler and Irmisch.⁴

Adrenaline and norepinephrine are (like dopamine) biogenic amines and catecholamines. They are continuously produced and metabolized in the body and are always present in small amounts in arterial blood.

Adrenaline is produced primarily in the adrenal medulla and, in small amounts, in chromaffin cells of other organs. Adrenaline helps the body adapt to stress, stimulates the heart, dilates cardiac and muscular arterioles, mobilizes glucose, and calms the intestines.

Norepinephrine acts as a hormone in the body. However, the norepinephrine in the body has no effect on the brain because it cannot cross the blood-brain barrier.

In the body, norepinephrine is produced primarily in sympathetic nerve endings and, to a lesser extent, in the adrenal medulla. Norepinephrine generally causes vasoconstriction (except in the coronary arteries) and increases both systolic and diastolic blood pressure.

Norepinephrine and epinephrine promote oxygen consumption, stimulate fat breakdown, and increase plasma free fatty acids (FFAs).⁵

2. Norepinephrine in the Brain (Neurotransmitter)¶

In the central nervous system, norepinephrine acts as a neurotransmitter.
With advancing age, humans, primates, and rodents lose 40 to 60 percent of their noradrenergic neurons in the nucleus coeruleus. However, no loss of norepinephrine was observed in the PFC of primates.⁶
Norepinephrine (like all monoamines) modulates the function of non-neuronal cells through a receptor-mediated process.³

2.1. What Is Regulated by Norepinephrine¶

The varying norepinephrine affinity of adrenoreceptors controls different phases of activity:⁷

• Sleep: The brain does not release norepinephrine⁸
• Calm alertness: α2 receptors are activated
• Active alertness, physical stress: α2 and α1 receptors are activated
• Stressful stress: α2-, α1-, and β-receptors are activated.

Norepinephrine regulates:

• Attention
  • 2 attention systems:⁹¹⁰ At rest, the two networks operate independently. When the dorsal network is activated (focused attention, concentration), it suppresses the ventral network to prevent reorientation toward distracting events
    • The dorsal frontoparietal attention network controls
      • Focusing attention on key, anticipated, and exploitable stimuli (concentration)
      • Linking stimuli and responses
      • Top-down attention control
      • Norepinephrine acts on the dorsal attention center.¹¹
    • The ventral frontoparietal attention network controls
      • Interrupting and resuming ongoing activities (easily distracted)
      • Redirecting attention to peripheral, unexpected (e.g., alarming), and explorable stimuli (task switching)
      • Destruction of norepinephrine receptors leads to increased distractibility¹²
      • Noradrenergic control via the locus coeruleus system¹³¹⁴
        • Locus coeruleus—phasic norepinephrine activates arousal-dependent sensory and cognitive processing of salient information, such as pain or startle stimuli, via the ventral attentional network¹⁵, thereby regulating various attentional functions during task performance.¹⁶
    • Norepinephrine modulates attention in two ways:
      • directly by improving the signal-to-noise ratio¹⁷¹⁸
      • Indirectly via mesocorticolimbic DA release¹⁷ More on the brain’s two attention centers ⇒ The dopaminergic and noradrenergic attention systems
• Vigilance¹⁹
  • Alertness in the form of sustained attention, in which the focus of attention is maintained over a longer period of time through mental effort
  • A key factor affecting performance under vigilance conditions is the monotony effect, which distinguishes the vigilance paradigm from tasks with higher cognitive demands
• Arousal
  • General level of arousal of the central nervous system. Characteristics include, for example, attention, alertness, and responsiveness.
• Activity i.e. general behavioral activation²⁰
• Working memory¹⁹
• Motivation²¹
• Perception of stimuli²²
• Modulation of the ascending reticular activating system (ARAS)¹⁹
• Pulse control²¹
• Inhibition²³
• Mood²¹
  • Norepinephrine helps limit mood swings²¹
• Memory
  • for emotions²¹
  • for aversive memories¹⁸
• executive functions²⁴
• increases risk tolerance²⁵
• makes one less critical²⁵
• increases alertness, reduces fatigue²⁵
• circadian rhythm
  • by influencing the gene expression of the clock genes PER1, PER2, and PER3²⁶
• increases sex drive²⁵
• boosts self-esteem²⁵
• reduces appetite²⁵
• is involved in stress symptoms¹⁷
  • sympathomimetic²⁵
    • dilates the bronchi (bronchodilation)
    • raises blood pressure
  • In cases of (generalized) anxiety disorder and PTSD, norepinephrine levels in the autonomic nervous system (specifically, the sympathetic nervous system) are elevated.²⁷²⁸
    • Norepinephrine agonists (e.g., yohimbine) intensify the anxiety (and stress) response²⁰
  • Norepinephrine is closely linked to the endocrine stress systems, particularly the CRH and ACTH systems²⁰ (autonomic nervous system, HPA axis)
  • Norepinephrine influences CRH release in the hypothalamus (HPA axis) via the abundant noradrenergic alpha-1 receptors found there, while CRH released from the hypothalamus, in turn (like stressors themselves), increases norepinephrine release in the locus coeruleus, which is then released into the PFC.²⁹
    • Endogenous opioids not only alleviate pain but also dampen the CRH-mediated noradrenergic stress response³⁰³¹
  • The locus coeruleus (the site of origin of norepinephrine) indirectly influences the sympathetic nervous system.³⁰
    • by which norepinephrine acts from there on neurons in the medulla oblongata, which in turn stimulate preganglionic neurons.³⁰
  • Acute stress increases norepinephrine levels³²
    • Amygdala and PFC (relevant to emotional experience).³²Chronic stress leads to persistently elevated norepinephrine levels and, consequently, to a downregulation Of the corresponding adrenoceptors (norepinephrine receptors) in
      • periaqueductal gray (relevant to behavioral control)³²
      • Hypothalamus³²
      • dorsomedial medulla oblongata (relevant for the control of autonomic functions)³²
    • In contrast, Rensing et al., citing the aforementioned sources, report a upregulation Of norepinephrine receptors in the limbic system³³
      Downregulation and upregulation are not necessarily mutually exclusive; rather, according to the norepinephrine receptor hypothesis, they can occur sequentially during different phases of a stress response and may act in opposite directions in different regions of the brain.
      According to this, upregulation would be typical of the final stage of depression, while downregulation corresponds to the first step (see Phases of Stress Development).
      ⇒ The Norepinephrine Receptor Hypothesis of Depression
    • Downregulation is a general response to excessively high levels of a neurotransmitter over an extended period and leads to desensitization of the respective receptors, with postsynaptic receptors decreasing first, followed by the presynaptic autoreceptors (which release the neurotransmitter). This disrupts the inhibition of neurotransmitter release. This results in sustained overactivity of the neurotransmitter-producing neurons (resistance phase). If the stressful situation persists, neurotransmitter production in the nerve cells breaks down (exhaustion phase). As a consequence, the receptors upregulate again.
      On Downregulation and Upregulation ⇒ Stress-related damage caused by early childhood or prolonged stress.
      About the phases of a stress response: ⇒ ADHD as a chronic stress regulation disorder.
  • Norepinephrine (along with CRH and vasopressin) influences ACTH secretion in the pituitary gland (HPA axis). ACTH is reduced by stimulation of the noradrenergic alpha-2 receptors and increased by stimulation of the noradrenergic beta receptors.²⁰
• Endogenous opioids can reduce the noradrenaline-stimulating effect of CRH in the locus coeruleus.³⁴
• Norepinephrine increases vasopressin secretion.³⁵

Norepinephrine is involved in various clinical conditions:³⁶

• post-traumatic stress disorder (PTSD)
• neurodegenerative diseases
  • Alzheimer’s
  • Parkinson’s
• Schizophrenia
• Depression
• ADHD
• ASD

3. Noradrenergic Communication in the Brain¶

The brain contains numerous communication systems through which specific brain regions exchange information with one another (similar to highways within the overall road network), each of which uses specific neurotransmitters.
Two of these communication systems are based on the exchange of information via norepinephrine (noradrenergic pathways).

3.1. Noradrenergic Systems of the Brain¶

3.1.1. Cortical Norepinephrine Pathway of the Locus Coeruleus¶

• Neurotransmitter: norepinephrine
• Origin: Norepinephrine production in the locus coeruleus
• Target: Many areas of the forebrain, hippocampus, amygdala, cerebellum, and spinal cord³⁷

The release of norepinephrine in the locus coeruleus is regulated by arousal.³⁸

• Sleep:
  • REM sleep:
    • no release of norepinephrine
  • Slow-wave sleep:
    • tonic: low norepinephrine release
• When arousal is low (drowsiness):
  • tonic: low norepinephrine release
  • phasic: low norepinephrine release
• Response to relevant stimuli while awake and at rest:
  • tonic: moderate
  • phasic: distinct
• when you’re stressed:
  • tonic: strong
  • phasic: low to dysregulated

3.1.2. Cortical-tegmental norepinephrine pathway¶

• Neurotransmitter: norepinephrine
• Origin: Norepinephrine production in the lateral tegmentum of the brainstem
• Target: Several regions of the basal forebrain, including the hypothalamus and amygdala³⁷

3.1.3. Distribution of norepinephrine via cortical capillaries¶

Noradrenergic terminals are located within the neurovascular unit in close proximity (less than 3 μm) to the cortical capillaries. This suggests that the intracortical microvessels receive central aminergic inputs.³

3.2. Brain Development and Norepinephrine¶

3.2.1. Disorders of the Development of Noradrenergic Systems¶

During its formation and postnatal development, the locus coeruleus is particularly vulnerable to certain types of damage:³⁹

• Hypoxia⁴⁰⁴¹
  • can cause morphological and cellular disorders in the cell nucleus during ontogenesis and postnatal development:⁴²
    • Increase in areas with granular cytoplasmic reticulum
    • Discoloration of the mitochondrial matrix
    • Reduction in the number of cristae
    • increased number of pores in the core membrane
    • no structural changes in the synaptic apparatus or in the neuronal processes
  • The locus coeruleus is more severely damaged by hypoxia than other monoaminergic nuclei⁴⁰
  • Damage caused by hypoxia, possibly as a consequence of maternal smoking⁴³
    • directly due to high CO levels in the mother’s blood
    • indirectly, through the vasoconstrictive effect of nicotine
  • Damage to the locus coeruleus caused by perinatal hypoxia increases the risk of mental disorders later in life⁴³⁴⁴
• Toxins³⁹
  • Bisphenol A (BPA)⁴⁵
    • Elevated norepinephrine levels in the cortex, hypothalamus, and thalamus in females⁴⁶
• Maternal malnutrition⁴⁷

3.2.2. Consequential impairments in brain development due to disorders of the noradrenergic systems¶

The brain’s norepinephrine system plays an important role in regulating and stimulating the formation and development of other areas of the CNS.³⁹ The projections of the locus coeruleus begin to form as early as the fetal stage and influence other brain regions. Noradrenergic cells begin to form as early as the 5th week of pregnancy.⁴⁸

Norepinephrine, as a neurotrophic factor, plays an important role in brain development:

• apparently promotes cell differentiation⁴⁹⁵⁰
• The correct expression and function of NET are important for the physiological neuronal differentiation of both noradrenergic and non-noradrenergic cells in the developing brain.⁵¹⁵²
• Differentiation and structural development of the cortex⁵³, the visual cortex (inhibitory influence)⁵⁴
• Differentiation of cortical neurons from layer IV to layer II⁵⁵
• Maturation of motor networks and the spinal cord⁵⁶
• Promotion of neurogenesis in the hippocampus⁵⁷](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751403/))⁵⁸
• Inhibition of neurogenesis in the periventricular hypothalamus and the periaqueductal midbrain (Weselek G, Keiner S, Fauser M, Wagenführ L, Müller J, Kaltschmidt B, Brandt MD, Gerlach M, Redecker C, Hermann A, Storch A (2020): Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche. Stem Cells. September 2020;38(9):1188-1201. doi: 10.1002/stem.3232. PMID: 32473039.))

4. Norepinephrine – Synthesis – Signaling Pathways¶

Norepinephrine is produced through the conversion of the amino acid tyrosine, which enters the central nervous system via the bloodstream. Tyrosine is gradually converted into norepinephrine by three enzymes. The first and most important enzyme is tyrosine hydroxylase (TOH). It converts the amino acid tyrosine into dopa.
The second enzyme, dopa decarboxylase (DDC), converts dopa into dopamine.
Dopamine is itself a neurotransmitter. It is also the substance from which norepinephrine is produced.
The enzyme dopamine-beta-hydroxylase (DBA) converts dopamine into norepinephrine. The norepinephrine is then (like any neurotransmitter) stored in the synaptic vesicles (reservoirs for neurotransmitters in the nerve endings) until it is activated by a nerve impulse and released.

5. Tonic and phasic norepinephrine¶

We have already covered the basics of tonic and phasic release, as well as extracellular levels of a neurotransmitter, in the section on dopamine under Tonic / Phasic / Extracellular Dopamine . We will therefore limit ourselves in the following to the specific characteristics of norepinephrine in this regard, based on the description by Holland et al.⁵⁹
The interplay between tonic and phasic activity enables adaptive behavior by promoting engagement with or disengagement from a task, depending on its importance and the expected reward or punishment.

5.1. Tonic Norepinephrine¶

Tonic norepinephrine activity depends on alertness (sleep/wakefulness) and the external environment (calm/stressful).³⁹
Tonic noradrenergic activity varies throughout the waking state. During restless behavior, LC activity was higher than during goal-directed behavior. A decrease in tonic norepinephrine release was associated with drowsiness, and a pause in tonic firing a few seconds later was associated with sleep.⁶⁰

Tonic and phasic norepinephrine firing are interrelated.
Low tonic activity under unloaded conditions

• enables an adequate, phasic release of norepinephrine from the locus coeruleus that is finely tuned to the demands (stimulus or task).⁶¹⁶²³⁸
• generally reduces neural responsiveness and is associated with an adaptive narrowing of attention to task-relevant stimuli⁶³
  Increased tonic norepinephrine release
• increases neural responsiveness throughout the cortex⁶³
• broadens attention to environmental stimuli regardless of their relevance to the task⁶³
• impaired the ability to distinguish stimuli from distractors. This led to more errors due to increased distractibility or increased signal-to-noise ratio. This, in turn, reduced participation in the tasks. In rats as well, stimulation of tonic norepinephrine firing resulted in increased decision noise and reduced engagement in the task.⁶⁴
• Stress-induced increased basal tonic firing in the nucleus coeruleus results in:³⁹
  • a heightened state of alertness and an improved ability to detect unexpected stimuli
  • difficulty transitioning to focused activity, which impairs the ability to concentrate on a specific goal

5.2. Phasic norepinephrine¶

Phasic norepinephrine activity is triggered by³⁹⁶⁰

• new or unexpected stimuli
• cognitive tasks that require concentration

Phasic norepinephrine activity is regulated by the outcome of task-related decision-making processes in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). Phasic norepinephrine activity is used to facilitate the behavior resulting from task-related decision-making processes and to optimize task performance. If the reward value of a task decreases, the locus coeruleus shifts to a tonic mode of activity, leading to a shift away from the current task and a search for alternative behaviors. Phasic and tonic norepinephrine release thus regulate performance optimization across different time scales.⁶⁵ For further reading: Devilbiss, Waterhouse.⁶⁶

In a visual-motor task involving rewards and punishments, noradrenergic phasic signals in monkeys had consequences for salient stimuli but not distractors. In trials with poor performance, the noradrenergic phasic response was reduced or absent. Phasic norepinephrine may serve to optimize behavioral responses and alertness to subsequent sensory stimuli.⁶⁰

When not actively performing tasks, the locus coeruleus returns to a tonic (constant, consistently low) firing rate.⁶⁰

5.3. Tonic and Phasic Norepinephrine in ADHD and ASD¶

Tonic and phasic norepinephrine firing can be detected based on pupil diameter.
The basal pupil diameter corresponds to tonic norepinephrine firing, and a change in pupil diameter corresponds to phasic noradrenergic activity. Phasic pupil dilation correlated with correct responses, while tonic pupil dilation correlated with periods of low reward value.⁶⁷ An increase in baseline pupil diameter correlated with a decrease in task utility and a disengagement from the task (exploration), while a decrease in baseline diameter accompanied by an increase in task-induced dilation correlated with engagement in the task (exploitation).⁶⁸
Studies in humans show that pupil diameter also reflects connectivity between frontoparietal, striatal, and thalamic brain regions.⁶⁹.

In neurodevelopmental disorders such as ADHD or ASD, the locus coeruleus exhibits basal hyperactivity with a higher tonic firing rate (as evidenced by an increased resting-state pupil diameter ( RSPD)), which impairs phasic discharges and, consequently, the focusing or shifting of attention. The attention deficits associated with neurodevelopmental disorders are likely the consequences of this imbalance.³⁹
In Alzheimer’s disease, pupil measurements also revealed increased tonic and decreased phasic norepinephrine activity.⁷⁰

5.3.1. Tonic and Phasic Norepinephrine in ADHD¶

ADHD is associated with hyperactivity in the locus coeruleus, particularly in the right hemisphere. The kinetics of pupil diameter reflect the neural activity of the locus coeruleus in relation to cognitive functions such as attention and arousal. Temporal patterns of pupil diameter provide unique insights. One study found asymmetrical pupil diameters that correlate with the severity of inattention, impulsivity, and hyperactivity in ADHD; this could be attributed to a left-right imbalance in locus coeruleus activity.⁷¹

5.3.1.1. Tonic Norepinephrine in ADHD¶

In contrast, in ADHD, it was found that

• an increased pupil diameter at rest (identical to ASS in this respect)^{7273 73} .
  • Stimulants further increased pupil size⁷⁴

5.3.1.2. Phasic Norepinephrine in ADHD¶

In cases of ADHD, it was found that

• a reduced (suppressed) pupillary response during a sustained auditory task⁷³
• a decrease in pupil size in response to an increased stimulus⁷²
  • Stimulants further reduced pupil dilation⁷⁴
• Reduced change in pupil diameter in response to light stimuli in both eyes and reduced constriction speed in the left eye in ADHD⁷⁵
  • Children with ADHD who respond well to stimulants showed either unusually large or unusually small pupil constrictions in response to a light stimulus, which tended to normalize when they took stimulants, Nonresponders tended to show more consistent values that changed little while on stimulants.⁷⁴
• reduced pupil dilation (as a sign of reduced access to brain capacity) during a resource-intensive task⁷⁶
• unchanged noradrenergic phasic pupil diameter responses⁷⁷ The extent of the changes in RSPD and EPDR were directly correlated with one another, supporting the hypothesis of global dysfunction of the LC-NA system.
• increased pupil dilation in response to social stimuli, such as happy faces⁷⁸

ADHD and ASD showed differences in visual orientation: atypical orientation toward relatively unexpected targets in ASD and atypical processing of warning cues in ADHD. The task-induced pupil dilation during visual orientation revealed:⁷⁹

• In ADHD, shorter latencies of pupillary dilation compared to ASD, ASD + ADHD, and controls
• In individuals with ASD, slower orienting responses to relatively unexpected spatial target stimuli, which were associated with greater pupil dilation amplitudes compared with people with ADHD and controls

The studies cited so far show inconsistent results. To date, no distinction has been made based on ADHD presentation patterns (subtypes).
A study found a link between reduced pupillary dilation responses to stimuli in children aged 8 to 13 and externalizing behaviors two years later.⁸⁰ We consider it plausible that this finding aligns with the reduced cortisol stress response observed in cases of externalizing symptoms (ADHD-HI, ADHD-C, as well as other externalizing disorders).

Externalizing symptoms are associated with reduced reactivity of the autonomic nervous system, which is also reflected in a reduced pupillary dilation response⁸¹ or a flattened error-related negativity (ΔERN)⁸²⁸³ as a predictor or biomarker of externalizing symptoms, e.g., in conduct disorder.⁸⁴

In contrast, internalizing disorders tend to be associated with increased autonomic reactivity and hyperarousal,⁸⁵ such as increased error-related negativity (ΔERN).⁸²⁸³
Unfortunately, studies on the reactivity of the autonomic nervous system in ADHD do not take into account the differences in the forms of presentation (subtypes) of ADHD,⁸⁶ even though these differences—as externalizing and internalizing variants—are glaringly obvious. As a result, the inconclusive results come as no surprise to us.

Stimulants increase arousal.⁸⁷ Kleberg et al. hypothesize that in ADHD—regardless of whether arousal is already reduced or increased—stimulants could make it easier for people with ADHD to respond to phasic stimuli by further increasing arousal. This could explain why stimulants may be beneficial in cases of both ADHD-related decreased and ADHD-related increased arousal.⁸⁰ This is consistent with a study by the same authors, which found that an auditory warning signal (which increases arousal) normalized subsequent performance in people with ADHD.⁸⁸

5.3.2. Tonic and phasic norepinephrine in ASS¶

5.3.2.1. Tonic Norepinephrine in ASS¶

Children with ASD have a larger resting pupil diameter (RSPD, a biomarker for increased tonic activity of the nucleus coeruleus) in ASD^77899091

5.3.2.2. Phasic Norepinephrine in ASS¶

Children with ASD exhibit abnormal changes in pupil diameter in response to stimuli or tasks (task/stimulus-evoked pupil dilation response, EPDR or SEPR, a biomarker for increased phasic norepinephrine firing in the nucleus coeruleus)^92937994

In several studies, the EPDR was observed in patients with ASD

• increased
  • in response to visual stimuli⁹⁴
  • in response to non-social stimuli^92959689
• reduced
  • in response to social cues⁹²
  • in an oddball paradigm with three stimuli⁹¹ The tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptoms.
  • In a visual working memory task, individuals with ASD showed reduced amplitudes of the task-induced pupillary response⁶³

In ASS, the pupil’s response to changes in brightness (luminance-adaptation pupillary response, LAPR) is also reduced.⁹²

The

6. Norepinephrine receptors¶

Norepinephrine receptors are also called adrenoceptors. The three types of norepinephrine receptors (adrenoceptors) differ based on their affinity for norepinephrine:⁷

• α1-adrenoceptors: moderate affinity for NA
• α2-adrenoreceptors: high affinity for NA
• β-adrenoceptors: low affinity for NA

Norepinephrine has the following effects:⁵⁹

• excitatory via postsynaptic α1- and β-adrenoceptors
  • low affinity
  • only when norepinephrine levels are high (acute stress)
• inhibitory via the primarily presynaptic α2-adrenoceptors
  • mainly in the PFC
  • highly selective
  • addressed even at low levels of norepinephrine
    (It is currently unclear to us why low norepinephrine levels activate the inhibitory autoreceptors; since that would lead to a further reduction in norepinephrine release even at low norepinephrine levels; presumably, α2-adrenoceptors do not have an inhibitory effect on norepinephrine release)

The effect of norepinephrine on adrenergic receptors depends on the region of the brain:⁹⁷

• α1-adrenoceptors:
  • frontal: impairs memory
  • posterior: improves memory
• α2-adrenoreceptors: high affinity for NA
  • frontal: improves memory
  • posterior: affects memory
• β-adrenoreceptors: low affinity for NA
  • frontal: does not affect memory
  • posterior: improves memory

Adrenoceptors are also found on astrocytes and oligodendrocytes, through which norepinephrine regulates intracellular Ca++ concentrations and energy metabolism in these cells.³

6.1. α-1-Adrenoceptors¶

• postsynaptic
• moderate norepinephrine affinity
  • Only when norepinephrine levels are high do α1 receptors become activated
• Effect of norepinephrine on the α1 receptor:
  • excitatory, by reducing potassium currents⁹⁸
  • Activation of phospholipase C
    • → Formation of inositol trisphosphate (IP3) (second messenger)
    • → Formation of diacylglycerol (DAG) (second messenger)

6.1.1. Alpha-1 Receptor Types:¶

6.1.1.1. α1-A-adrenoceptor¶

• Agonists:
  * Adrenaline
  * Norepinephrine
  * Phenylephrine
  * A-61603
  * Oxymetazoline
• Antagonists:
  * Prazosin
  * Doxazosin
  * Terazosin
  * Alfuzosin
  * Urapidil
  * Sertraline
  * Tamsulosin
  * 5-Methylurapidil
  * B8805-033
  * SNAP 5089
  * RS-17053

6.1.1.2. α1-B-adrenoceptor¶

• Agonists:
  * Adrenaline
  * Norepinephrine
  * Phenylephrine
• Antagonists:
  * Prazosin
  * Doxazosin
  * Terazosin
  * Alfuzosin
  * Urapidil
  * Sertraline
  * Tamsulosin
  * Chloroethylclonidine
  * L-765314

6.1.1.3. α1-C-adrenoceptor (1-D)¶

• Agonists:
  * Adrenaline
  * Norepinephrine
  * Phenylephrine
  * Buspirone
• Antagonists:
  * Prazosin
  * Doxazosin
  * Terazosin
  * Alfuzosin
  * Urapidil
  * Sertraline
  * Tamsulosin
  * BMY 7378
  * MDL 73005EF

6.1.1.4. α1-L-adrenoceptor¶

• It is unclear whether this is a distinct subtype or a conformational variant of the alpha-1A receptor
• Agonists:
  * Adrenaline
  * Norepinephrine
  * Phenylephrine
  * A-61603
• Antagonists:
  * Prazosin
  * Doxazosin
  * Terazosin
  * Alfuzosin
  * Urapidil
  * Sertraline
  * Tamsulosin

6.1.2. α1-Adrenoceptor Agonists¶

• α1-receptor agonists can mimic the effects of high levels of NA or DA⁹⁹
  • Phenylephrine
  • SKF81297 in high concentration
• Shut down PFC⁹⁹¹⁰⁰
  • a model similar to that of cortisol, which regulates the “normal” mode of the HPA axis and only shuts down the HPA axis via the low-affinity glucocorticoid receptors when cortisol levels are high enough to fully saturate the MR

6.1.3. α1-Adrenoceptor Antagonists¶

• improve sustained attention and performance on stop-signal tasks¹⁰¹

6.2. α2 Receptors¶

• predominantly presynaptic on norepinephrine-producing cells⁵⁹¹⁰²

• high norepinephrine affinity
  are therefore activated even when norepinephrine levels are low

• Effect of norepinephrine on the α-2 receptor: inhibitory, by increasing potassium currents¹⁰³

• α2ARs modulate the inhibitory effect of P-neurons.

• α2ARs form receptor heteromers with D4R¹⁰⁴

  • D4R thereby modulates the inhibitory effect of P-neurons
    • This could explain at least part of the protective effect of D4.4R in ADHD, as well as the increased susceptibility to developing ADHD mediated by D4.7R.
    • Cortical α2AR-D4.4R heteromers could function as norepinephrine sensors that are activated at high norepinephrine levels and then inhibit the activation of the α2AR within the heteromer, which in turn reduces the α2AR-mediated inhibition of P-neurons.
    • In the α2AR-D4.7R heteromer, the increased potency of norepinephrine for α2AR (via D4.7R) facilitates the α2AR-mediated inhibitory effect on P-neurons

6.2.1. Alpha-2-Adrenoceptor Types¶

6.2.1.1. α2-A-adrenoceptor¶

• primarily presynaptic⁵⁹

• high norepinephrine affinity

• Agonists: norepinephrine and dopamine

  • Norepinephrine
    • increases activity in the PFC
    • reduces norepinephrine release (autoreceptor = negative feedback)
    • phasic stimulation in emergency situations¹⁰⁵
      • blocks beta-2 receptors
  • Dopamine
    • Dopamine can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus^106107108

• widespread throughout the brain¹⁰⁹

  • in the PFC and locus coeruleus
  • In the cortex, it is preferentially localized postsynaptically in P neurons of the deep layers¹¹⁰¹¹¹
  • potentially colocalized with D4R (heteromers)¹⁰⁴
    • α2AR-D4R heteromers present in significant quantities in the mouse cortex¹¹²

• Activation of cortical postsynaptic α2AR produced two opposing neuronal effects:¹⁰⁴

  • both depend on a Gi-protein-mediated decrease in cAMP production
  • There are likely two distinct functional populations of α2AR:
    • stimulating effect
      • depending on the inactivation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN)¹¹³
      • is thought to mediate the therapeutic effect of α2AR agonists by counteracting the cortical frontal hypoactivity associated with ADHD¹¹⁰
    • inhibitory effect
      • dependent on the inactivation of AMPA receptors¹¹⁴¹¹⁵
      • could be mediated by a distinct population of α2ARs, which acts as a protective mechanism against overstimulation caused by high norepinephrine release under stressful conditions¹¹⁴

• α-2 agonists
  Act on presynaptic α-2A receptors: Alterations in excitation mechanisms in the basal forebrain and hypothalamus

  • Norepinephrine
  • Dopamine
  • Thyronamine
  • [3H]RX821002¹¹⁶

• α-2 antagonists cause

  • Improved sustained attention and response inhibition¹⁰¹

6.2.1.2. α2-B-adrenoceptor¶

• occurs primarily in the thalamus¹⁰⁹
• Sleep regulation
• α-2 agonists have a sedative effect and promote sleep

6.2.1.3. α2-C adrenoreceptor¶

• widespread throughout the brain¹⁰⁹
  • PFC
  • Locus coeruleus

6.3. β-Adrenoreceptors¶

• postsynaptic
• low norepinephrine affinity
• Only high levels of norepinephrine activate β-receptors
  • A mechanism similar to that of cortisol, which regulates the “normal” mode of the HPA axis by binding to high-affinity mineralocorticoid receptors and only shuts down the HPA axis when high levels bind to low-affinity glucocorticoid receptors
  • It is still unclear what is inhibited by β-receptors.
  • Stress-induced activation of microglia appears to be mediated by norepinephrine via β1- and β2-adrenoceptors, but not via β1-adrenoceptors or α-adrenoceptors.¹¹⁸
• Norepinephrine’s effect on the β-receptor: stimulatory, by reducing potassium currents.⁹⁸
• β-antagonists (beta blockers)
  • result in improved sustained attention and performance on stop-signal tasks (SST).¹⁰¹
  • increase impulsivity in healthy participants⁵⁹

6.3.1. β-1-Adrenoreceptor¶

• in the heart, kidneys, adipose tissue, and other tissues
• higher affinity for adrenaline than for norepinephrine
• cAMP feedback loop
  • Beta 1 increases cAMP synthesis
  • High levels of cAMP phosphorylate the serine and threonine residues of the beta-1 receptor, causing it to desensitize
• Increased cardiac strength and heart rate
• Lipolysis
• increased release of renin
  • → Stimulation of the renin-angiotensin-aldosterone system
  • → Increase in peripheral blood pressure
• β1-agonists
  • Adrenaline
  • Isoprenaline (isoproterenol)
  • Norepinephrine
  • Xamoterol
  • Denopamine
• β1-blockers
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propranolol
  • Metoprolol
  • Bisoprolol
  • Atenolol
  • Betaxolol

6.3.2. β-2-Adrenoreceptor¶

• Relaxation of the smooth muscles in the bronchi, uterus, blood vessels, and intestines
• Often found in the hippocampus of the brain¹¹⁹
  • A β2-receptor gene variant prolongs NA binding and is observed more frequently in PTSD¹¹⁹
• β2-agonists
  • Adrenaline
  • Isoprenaline (isoproterenol)
  • Norepinephrine
  • Salbutamol
  • Salmeterol
  • Clenbuterol
  • Terbutaline
  • Formoterol
  • Fenoterol
• β2-blockers
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propranolol
  • ICI 118551

6.3.3. β3-Adrenoceptor¶

• Lipolysis and thermogenesis in brown adipose tissue
• β3 agonists
  • Adrenaline
  • Isoprenaline (isoproterenol)
  • Norepinephrine
  • Amibegron
  • Mirabegron
  • Solabegron
• Antagonists
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propranolol
  • SR59230A

6.3.4. β4-Adrenoceptor¶

It is unclear whether a distinct beta-4 receptor type exists or whether this is an affinity state of the beta-1 receptor.

6.4. Norepinephrine also binds to dopamine D2-type receptors (D2, D3, D4)¶

Norepinephrine binds simultaneously to D2-type receptors with varying affinities: D3R > D4R ≥ D2SR ≥ D2LR.¹²⁰
Dopamine, in turn, can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus.^106107108

7. Reuptake and Breakdown of Norepinephrine¶

7.1. (Re)uptake of norepinephrine¶

7.1.1. Norepinephrine transporter (NET)¶

Norepinephrine transporters (like all transporters) are always located at the presynapse and reuptake neurotransmitters into the cell. Norepinephrine transporters are always found on noradrenergic cells.
In addition to norepinephrine, the norepinephrine transporter also reabsorbs dopamine. In ADHD, the norepinephrine transporter appears to be reduced in the attentional networks of the right hemisphere of the brain.¹²¹

7.1.2. Plasma Membrane Monoamine Transporter (PMAT)¶

Norepinephrine is also taken up by the plasma membrane monoamine transporter (PMAT), although to a much lesser extent than dopamine. This transporter is also known as human equilibrative nucleoside transporter-4 (hENT4). It is encoded by the SLC29A4 gene. Its binding affinity is lower than that of DAT or NET. It binds dopamine and serotonin with high affinity and, to a much lesser extent, norepinephrine, epinephrine, and histamine.¹²²

7.1.3. Organic Cation Transporters (OCT)¶

Norepinephrine (and, to a lesser extent, dopamine) is further taken up from the extracellular space by the organic cation transporters (OCT1, OCT2, OCT3). These are also referred to as solute carrier family 22 members 1, 2, and 3 or extraneuronal monoamine transporters (EMT). OTC2 and OTC3 are found in nerve cells and astrocytes and bind histamine > norepinephrine and epinephrine > dopamine > serotonin.¹²² Unlike with DAT and NET, uptake does not occur into the presynaptic cell but rather into glial cells. There, dopamine and norepinephrine are broken down by COMT into methoxytyramine.¹²³
OCT3 appears to occur primarily in peripheral tissues and barely in the brain.¹²²

The coding genes are:¹²⁴

• OCT1: SLC22A1
• OCT2: SLC22A2
• OCT3: SLC22A3

Examples of OCT antagonists include:¹²³

• Amantadine
• Memantine

7.2. Breakdown of Norepinephrine Through Metabolism¶

While norepinephrine transporters and dopamine transporters facilitate the reuptake of norepinephrine from the synaptic cleft back into the presynaptic cell, where it is repackaged into vesicles via VMAT2 transporters, dopamine is also broken down through conversion into other substances. The primary enzymes involved in this process are COMT and MAO-B.

7.2.1. PFC: Norepinephrine Breakdown by COMT¶

In the PFC in particular, norepinephrine is broken down not only through reuptake by NET but also, and especially, by the enzyme catechol-O-methyltransferase (COMT).

For details, see => Dopamine Breakdown by COMT in the article => Dopamine Reuptake and Breakdown.

7.2.1.1. COMT gene variants alter norepinephrine levels in the PFC¶

For details, see => Dopamine Breakdown by COMT in the article => Dopamine Reuptake and Breakdown.

7.2.1.2. Estrogen reduces COMT-mediated dopamine degradation in the PFC¶

For details, see => Dopamine Breakdown by COMT in the article => Dopamine Reuptake and Breakdown.

7.2.2. Breakdown of norepinephrine by monoamine oxidase (MAO-A)¶

Norepinephrine (like epinephrine) is broken down by MAO-A. Dopamine, on the other hand, is broken down by MAO-B.¹²³

7.3. Norepinephrine Breakdown by Diffusion¶

In the DAT-KO mouse, inhibition of serotonin transporters, norepinephrine transporters, MAOA, or COMT did not alter dopamine degradation in the striatum of the DAT-KO mouse. In the absence of DAT in the striatum, this degradation appears to occur primarily through diffusion.¹²⁵ This is likely to apply to norepinephrine as well.

8. What Regulates Norepinephrine¶

8.1. Mental and Physical Activity¶

Norepinephrine and epinephrine levels are elevated by mental activity just as much as by physical activity.

• In the case of an unpleasant, under-challenging task, levels of norepinephrine and epinephrine are also elevated; however, they are far higher in the case of an overwhelming task that is perceived as equally unpleasant.
• When performing a boring, under-stimulating task, participants with higher adrenaline levels performed better than those with lower adrenaline levels. In contrast, when performing a challenging, over-stimulating task, participants with lower adrenaline levels performed better.⁵
• Optimal norepinephrine signaling is dependent on a specific level of norepinephrine. Too little norepinephrine, just like too much, impairs noradrenergic signaling.⁵⁹ This corresponds to the well-known inverted-U model, which also applies to dopamine and serotonin.
• By influencing the ARAS, norepinephrine is linked to different increments of arousal.
  The level of arousal helps regulate behavior. Too little arousal (under-activation) and too much arousal (stress) impair performance. Individuals therefore strive to achieve their optimal level of arousal. This arousal is regulated by the noradrenergic system.⁸
  More on the mechanisms of activation (ARAS, etc.): ⇒ Activation from a neurological perspective

8.2. Stress¶

Electric shocks increase the release of adrenaline and norepinephrine, and the less control the people with ADHD have over this process, the greater the increase. Various stressful events increase norepinephrine release, particularly in the hypothalamus, the amygdala, and the locus coeruleus.¹²⁶ This explains why increased norepinephrine release is associated with the provocation of negative emotions such as anxiety and/or fear.¹²⁷

High adrenaline levels correlate with faster decision-making and fewer errors on cognitive tests, while low adrenaline levels correlate with slower decision-making and higher error rates.⁵

Cortisol exerts an inhibitory effect not only on the HPA axis but also on the locus coeruleus and, consequently, on norepinephrine release in the CNS (negative feedback). If this inhibition (due to hypocortisolism) is impaired, the person with ADHD lacks an important “stress brake.”¹²⁸
As with dopamine, it is not merely the presence or absence of the neurotransmitter norepinephrine that matters; rather, a distinction must be made between phasic (short-term) and tonic (long-term) presence.
Increased phasic activity in the locus coeruleus results in good attention.
In contrast, increased tonic norepinephrine activity leads to poorer performance.¹⁷
Clonidine is thought to enhance phasic norepinephrine activity in the locus coeruleus.¹⁷ This should therefore also apply to guanfacine.

8.3. Fever¶

Fever affects the noradrenergic system.
It has been reported that some people with ADHD experience fewer or no autistic symptoms when they have a fever.³⁶ ASD symptoms are mediated, among other things, by the noradrenergic system.

8.4. Other Factors Affecting Norepinephrine¶

• Bombesin
  • Bombesin, when administered intracerebroventricularly (i.c.v.), induces the secretion of norepinephrine and epinephrine from the adrenal medulla of rats.¹²⁹ CB1R agonists inhibit this effect, while CB1R antagonists enhance it.
• CRF
  • The stress hormone CRF increases norepinephrine and epinephrine via CB1R¹³⁰

9. Treatment Options for Noradrenergic Disorders¶

9.1. Medications¶

Norepinephrine reuptake inhibitors increase the availability of norepinephrine in the synaptic cleft by inhibiting the problematic overactivity of norepinephrine reuptake transporters (e.g., in ADHD).
Stimulants (amphetamine-based medications, MPH, and atomoxetine) act as dopamine reuptake inhibitors and also increase the production of dopamine and norepinephrine, as well as, to a lesser extent, serotonin.
Stimulants exert dopaminergic effects on the nucleus accumbens and improve symptoms of hyperactivity and self-initiation/reinforcement processes, while problems with response delay and working memory are mediated by noradrenergic effects of the locus coeruleus on the PFC. The effects of stimulants on attention and behavioral control are mediated by dopaminergic and noradrenergic mechanisms.¹³¹
While levels of norepinephrine, like dopamine, are reduced in the PFC in ADHD, norepinephrine levels are elevated in the PFC in PTSD, which (above a certain level) deactivates the PFC and activates the amygdala; this is why PTSD is typically treated with alpha-1 or beta-adrenoceptor antagonists, which counteract the deactivation of the PFC caused by excessive norepinephrine.¹⁰⁹
Korsakoff syndrome is a disorder characterized by marked, persistent impairment of short- and long-term memory (amnestic disorder) due to thiamine deficiency, which most often results from the consequences of chronic alcohol consumption. In Korsakoff’s syndrome, levels of MHPG—a metabolite of norepinephrine—in the cerebrospinal fluid are reduced, which correlates with impaired short-term memory. The alpha-2 receptor agonist clonidine improves memory and attention deficits in Korsakoff syndrome, whereas it worsens them in healthy individuals.¹³²

9.2. Non-pharmacological treatment¶

9.2.1. Structured Daily Routine (i.e. break schedule)¶

The brain’s noradrenergic system is completely deactivated during sleep. Upon waking, it is activated by the locus coeruleus.

The locus coeruleus’ ability to regulate activation can reportedly be trained through a clear daily rhythm with appropriate breaks (not imposed, but sensibly self-imposed and consistently followed).⁸

10. Disorders of the Norepinephrine System¶

10.1. Norepinephrine in ADHD¶

Norepinephrine has the second-greatest influence on ADHD, after dopamine.

The noradrenergic posterior attention center is also responsible for regulating motivation, mood, and emotional memory.
It must be distinguished from the dopaminergic-controlled anterior attention center.
⇒ The dopaminergic and noradrenergic attention centers

Only the ADHD symptom of impaired inhibition of executive functions is mediated dopaminergically by the striatum, whereas impaired inhibition of emotional regulation is caused noradrenergically by the hippocampus.¹³³ Therefore, only the former is amenable to dopaminergic treatment.
Emotion regulation and affect control, on the other hand, are reportedly better treated with noradrenergic agents.

The levels of norepinephrine metabolites (NE breakdown products) in urine return to normal during and after puberty, in parallel with the decline in (childhood-typical) ADHD-HI symptoms. This could be an indication of delayed brain maturation in ADHD.¹³⁴
Such a delay in brain maturation was observed with above-average frequency in carriers of the DRD4 7R polymorphism¹³⁵ Whether this represents a pathological delay in brain maturation or the prolonged brain maturation typical of highly gifted individuals (⇒ Giftedness and ADHD) remains an open question. High sensitivity is associated with the DRD4 7R polymorphism as a risk/opportunity gene. For more on this, see ⇒ How ADHD Develops: Genes + Environment.

The norepinephrine transporter, which also takes up dopamine, appears to be reduced in the attention networks of the right hemisphere of the brain in ADHD.¹²¹

A study replicated findings from other studies showing that children with ASD exhibit increased tonic (resting pupil diameter) and decreased phasic (PDR and ERP) activity of the nucleus coereus-norepinephrine system. The tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptoms.⁹¹

10.2. Norepinephrine in ASS¶

See the sections above on tonic norepinephrine in ASS and phasic norepinephrine in ASS.