Noradrenaline

Adrenaline and noradrenaline are hormones that are continuously produced and metabolized in the body (= peripherally). Adrenaline is mainly produced in the adrenal medulla and supports the body’s stress response. Noradrenaline (norepinephrine, NE) is mainly generated in sympathetic nerve endings. Adrenaline and noradrenaline promote oxygen metabolism and activate the breakdown of fat.

Noradrenaline in the brain as a neurotransmitter has a role in behavior and cognition, such as memory, learning, attention, vigilance, mood and motivation, in addition to its long-known influence on arousal, alertness during wakefulness and the recognition of sensory signals.¹²
Noradrenaline influences the reticular activating system and impulse control. The release of noradrenaline in the brain is influenced by stress or sleep, for example. The noradrenaline level can be increased by mental or physical activity.

In ADHD, noradrenaline has the second greatest influence after dopamine. It plays a role in the attention centers of the brain and influences motivation, mood and memory. It is suspected that ADHD is associated with a brain maturation delay that is accompanied by increased noradrenaline activity in the brain. The amount of noradrenaline metabolites in the urine normalizes with age.
Like dopamine, noradrenaline is also a neurotrophic factor, i.e. it influences brain development and neuroplasticity.

There are different types of noradrenergic receptors, the so-called adrenoceptors: α1, α2 and β receptors. These receptors can be activated by agonists or blocked by antagonists. Noradrenaline also binds to some dopamine receptors, just as dopamine binds to some adrenoceptors.

• 1. Adrenaline and noradrenaline in the body (hormone)
• 2. Noradrenaline in the brain (neurotransmitter)
  • 2.1. Control ranges of noradrenaline
• 3. Noradrenergic communication of the brain
  • 3.1. Noradrenergic systems of the brain
    • 3.1.1. Cortical noradrenaline pathway of the locus coeruleus
    • 3.1.2. Cortical-tegmental noradrenaline pathway
  • 3.2. Brain development and noradrenaline
    • 3.2.1. Disorders in the development of noradrenergic systems
    • 3.2.2. Consequential disorders of brain development due to disorders of noradrenergic systems
• 4. Noradrenaline - Development - Communication pathways
• 5. Tonic and phasic noradrenaline
  • 5.1. Tonic noradrenaline
  • 5.2. Phasic noradrenaline
  • 5.3. Tonic and phasic noradrenaline in ADHD and ASD
    • 5.3.1. Tonic and phasic noradrenaline in ADHD
      • 5.3.1.1. Tonic noradrenaline in ADHD
      • 5.3.1.2. Phasic noradrenaline in ADHD
    • 5.3.2. Tonic and phasic noradrenaline in ASA
      • 5.3.2.1. Tonic noradrenaline with ASA
      • 5.3.2.2. Phasic noradrenaline with ASA
• 6. Noradrenaline receptors
  • 6.1. α-1-Adrenoceptors
    • 6.1.1. Alpha 1 receptor types:
      • 6.1.1.1. α-1-A adrenoceptor
      • 6.1.1.2. α-1-B adrenoceptor
      • 6.1.1.3. α-1-C adrenoceptor (1-D)
      • 6.1.1.4. α-1-L-adrenoceptor
    • 6.1.2. α1-Adrenoceptor agonists
      • 6.1.3. α1-Adrenoceptor antagonists
  • 6.2. α-2 Receptors
    • 6.2.1. Alpha 2 adrenoceptor types
      • 6.2.1.1. α-2-A adrenoceptor
      • 6.2.1.2. α-2-B-adrenoceptor
      • 6.2.1.3. α-2-C adrenoceptor
  • 6.3. β-Adrenoceptors
    • 6.3.1. β-1-Adrenoceptor
    • 6.3.2. β-2-Adrenoceptor
    • 6.3.3. β-3-Adrenoceptor
    • 6.3.4. β-4-Adrenoceptor
  • 6.4. Noradrenaline also addresses dopamine D2-type receptors (D2, D3, D4)
• 7. Reuptake and breakdown of noradrenaline
  • 7.1. (Re)uptake of noradrenaline
    • 7.1.1. Noradrenaline transporter (NET)
    • 7.1.2. Plasma membrane monoamine transporter (PMAT)
    • 7.1.3. Organic cation transporters (OCT)
  • 7.2. Noradrenaline degradation through metabolization
    • 7.2.1. PFC: Noradrenaline degradation by COMT
      • 7.2.1.1. COMT gene variants alter noradrenaline levels in the PFC
      • 7.2.1.2. Estrogen reduces dopamine degradation by COMT in the PFC
    • 7.2.2. Noradrenaline degradation by monoamine oxidase (MAO-A)
  • 7.3. Noradrenaline degradation through diffusion
• 8. Regulation of noradrenaline
  • 8.1. Mental and physical activity
  • 8.2. Stress
  • 8.3. Fever
• 9. Treatment options for noradrenergic disorders
  • 9.1. Medication
  • 9.2. Non-drug treatment
    • 9.2.1. Structured daily routine (i.e. break rhythm)
• 10. Disorders of the noradrenaline system
  • 10.1. Noradrenaline in ADHD
  • 10.2. Noradrenaline with ASA

1. Adrenaline and noradrenaline in the body (hormone)¶

For an overview, see Hässler, Irmisch.³

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

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

Noradrenaline acts as a hormone in the body. However, noradrenaline in the body has no influence on the brain because it cannot cross the blood-brain barrier.

In the body, noradrenaline is mainly generated in sympathetic nerve endings and also in small amounts in the adrenal medulla. Noradrenaline generally has a vaso-constructive effect (except on the coronary arteries) and increases both systolic and diastolic blood pressure.

Noradrenaline and adrenaline promote oxygen turnover, activate the breakdown of fat and increase the free fatty acids (FFA) in the plasma.⁴

2. Noradrenaline in the brain (neurotransmitter)¶

Noradrenaline acts as a neurotransmitter in the CNS.
With increasing age, 40 to 60 % of the noradrenergic neurons in the nucleus coeruleus are lost in humans, primates and rodents. In primates, however, there was no loss of noradrenaline in the PFC.⁵

2.1. Control ranges of noradrenaline¶

The different noradrenaline affinity of the adrenoceptors controls different phases of activity:⁶

• Sleep: no noradrenaline is released in the brain⁷
• Calm alertness: α2 receptors are activated
• Active alertness, physical stress: α2 and α1 receptors are activated
• Stress: α2, α1 and β receptors are activated.

Regulates noradrenaline:

• Attention
  • 2 attention systems:⁸⁹ At rest, both networks act separately. Activated dorsal network (focused attention, concentration) suppresses ventral network to prevent reorientation to distracting events
    • The dorsal frontoparietal attention network controls
      • Focusing attention on central, expected and exploitable stimuli (concentration)
      • Linking stimuli and reactions
      • Top-down attention control
      • Noradrenaline acts on the dorsal attention center.¹⁰
    • The ventral frontoparietal attention network controls
      • Interruption of ongoing activities and their resumption (distractibility)
      • Redirecting attention to peripheral, unexpected (e.g. alarming) and explorable stimuli (task switching)
      • Destruction of noradrenaline receptors causes increased distractibility¹¹
      • Control noradrenergic via locus coeruleus system¹²¹³
        • Locus coeruleus - phasic noradrenaline activates the arousal-dependent sensory and cognitive processing of conspicuous information, such as pain or startle stimuli¹⁴, via the ventral attention network and thereby regulates various attention functions during task execution.¹⁵
    • Noradrenaline modulates attention in 2 ways:
      • Directly via improvement Signal-to-noise ratio¹⁶¹⁷
      • Indirectly via mesocorticolimbic DA release¹⁶ More on the two attention centers of the brain ⇒ The dopaminergic and noradrenergic attention systems
• Vigilance¹⁸
  • Alertness in the form of sustained attention, in which the focus of attention is to be maintained over a longer period of time using mental effort
  • A key aspect of performance under vigilance conditions is the monotony effect, which distinguishes the vigilance paradigm from tasks with higher cognitive demands
• Arousal
  • General degree of activation of the central nervous system. Characteristics are e.g. attention, alertness, readiness to react.
• Activity i.e. general behavioral activation¹⁹
• Working memory¹⁸
• Motivation²⁰
• Stimulus perception²¹
• Influencing the ascending reticular attention system (ARAS, ascending reticular activating system)¹⁸
• Pulse control²⁰
• Inhibition²²
• Mood²⁰
  • Noradrenaline limits mood swings²⁰
• Memory
  • For feelings²⁰
  • For aversive memory content¹⁷
• Executive functions²³
• Increases willingness to take risks²⁴
• Makes less critical²⁴
• Increases alertness, reduces tiredness²⁴
• Circadian rhythm
  • By influencing the gene expression of the clock genes PER1, PER2, PER3²⁵
• Increases sex drive²⁴
• Increases self-esteem²⁴
• Reduces appetite²⁴
• Is involved in stress symptoms¹⁶
  • Sympathomimetic²⁴
    • Expands the bronchi (bronchodilation)
    • Increases blood pressure
  • In (generalized) anxiety disorder and PTSD, the noradrenaline level in the autonomic nervous system (here: sympathetic nervous system) is increased ²⁶²⁷
    • Noradrenaline agonists (e.g. yohimbine) increase the anxiety (and stress) response¹⁹
  • Noradrenaline is closely linked to the endocrine stress systems, in particular the CRH and ACTH systems¹⁹(Vegetatives Nervensystem, HPA-Achse)
  • Noradrenaline influences CRH release in the hypothalamus (HPA axis) via frequent noradrenergic alpha1 receptors there, while CRH from the hypothalamus in turn (like stressors themselves) increases noradrenaline release in the locus coeruleus, which is released into the PFC²⁸
    • Endogenous opioids attenuate not only pain but also the noradrenergic stress response mediated by CRH²⁹³⁰
  • The locus coeruleus (the site of origin of noradrenaline) indirectly addresses the sympathetic nervous system²⁹
    • From there, norepinephrine influences neurons in the medulla oblongata, which in turn stimulate preganglionic neurons.²⁹
  • Acute stress increases the noradrenaline level³¹
    • Amygdala and PFC (relevant for emotional experience).³¹Permanent stress leads to permanently elevated noradrenaline levels and, consequently, to downregulation of the corresponding adrenoceptors (noradrenaline receptors) in
      • Periaqueductal gray (relevant for behavior control)³¹
      • Hypothalamus³¹
      • Dorsomedial medulla oblongata (medulla oblongata; relevant for control of autonomic functions)³¹
    • In contrast, Rensing et al, citing the aforementioned sources, report upregulation of noradrenaline receptors in the limbic system³²
      Downregulation and upregulation are not necessarily mutually exclusive but, according to the noradrenaline receptor hypothesis, can occur one after the other during different phases of a stress reaction and be in opposite directions in different regions of the brain.
      Upregulation would then be typical for the final state of depression, while downregulation corresponds to the first step (see phases of stress development).
      ⇒ Noradrenaline receptor hypothesis of depression
    • Downregulation is a general reaction to a neurotransmitter level that is too high for too long and leads to a desensitization of the respective receptors, whereby first the postsynaptic receptors and then the presynaptic autoreceptors (which release the neurotransmitter) decrease. This disrupts the inhibition of the release of the neurotransmitter. This results in a permanent overactivity of the neurotransmitter neurons (resistance phase). If the stress situation continues, neurotransmitter production in the nerve cells collapses (exhaustion phase). Consequences of this are that the receptors upregulate again.
      For downregulation and upregulation ⇒ Stress damage due to early childhood or prolonged stress.
      The phases of a stress reaction: ⇒ ADHD as a chronic stress regulation disorder.
  • Noradrenaline influences (alongside CRH and vasopressin) the release of ACTH in the pituitary gland (HPA axis). ACTH is reduced by stimulation of the noradrenergic alpha2 receptors and increased by stimulation of the noradrenergic beta receptors.¹⁹
• The body’s own opioids can reduce the noradrenaline-stimulating effect of CRH in the locus coeruleus.³³
• Noradrenaline increases the release of vasopressin.³⁴

Noradrenaline is involved in various disorders:³⁵

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

3. Noradrenergic communication of the brain¶

The brain contains a number of communication systems by means of which certain areas of the brain exchange information with each other (similar to highways within the entire road network) and which each use certain neurotransmitters.
Two of these communication systems are based on an exchange of information via noradrenaline (noradrenergic pathways).

3.1. Noradrenergic systems of the brain¶

3.1.1. Cortical noradrenaline pathway of the locus coeruleus¶

Source³⁶

• Neurotransmitter: Noradrenalin
• Origin: Noradrenaline formation in the locus coeruleus
• Target: Many areas of the forebrain, hippocampus, amygdala, cerebellum and spinal cord

The release of noradrenaline in the locus coeruleus is controlled by arousal.³⁷

• Sleep:
  • REM sleep:
    • No noradrenaline release
  • Slow-wave sleep:
    • Tonic: little noradrenaline release
• For low arousal (drowsiness):
  • Tonic: little noradrenaline release
  • Phasic: little noradrenaline release
• Reaction to relevant stimuli in an unstressed waking state:
  • Tonic: moderate
  • Phasic: clear
• In case of stress:
  • Tonic: strong
  • Phasic: little to dysregulated

3.1.2. Cortical-tegmental noradrenaline pathway¶

Source³⁶

• Neurotransmitter: Noradrenalin
• Origin: Noradrenaline formation in the lateral tegmentum of the brain stem
• Target: Several areas of the basal forebrain incl. hypothalamus and amygdala

3.2. Brain development and noradrenaline¶

3.2.1. Disorders in the development of noradrenergic systems¶

During formation and postnatal development, the locus coeruleus is particularly susceptible to certain types of damage:³⁸

• Hypoxia³⁹⁴⁰
  • can cause morphological and cellular disorders of the nucleus during ontogenesis and postnatal development:⁴¹
    • Increase in areas with granulated 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 and on the neuronal processes
  • Locus coeruleus is more severely damaged by hypoxia than other monoamine nuclei³⁹
  • Damage due to hypoxia possibly as a result of maternal smoking⁴²
    • directly due to high CO content in the mother’s blood
    • indirectly through the vasoconstrictive effect of nicotine
  • Damage to the locus coeruleus due to perinatal hypoxia increases the risk of mental disorders in life⁴²⁴³
• Toxins³⁸
  • Bisphenol A (BPA)⁴⁴
    • Noradrenaline levels in the cortex, hypothalamus and thalamus increased in females⁴⁵
• Malnutrition of the mother⁴⁶

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

The noradrenaline system of the brain plays an important role in regulating and stimulating the formation and development of other areas of the CNS.³⁸ The projections of the locus coeruleus are already formed in the fetus and have an effect on other brain regions. Noradrenergic cells form as early as the 5th week of pregnancy.⁴⁷

As a neurotrophic factor, noradrenaline plays an important role in brain development:

• apparently promotes cell differentiation⁴⁸⁴⁹
• correct NET expression and function is important for the physiological neuronal differentiation of both noradrenergic and non-noradrenergic cells in the developing brain.⁵⁰⁵¹
• Differentiation and structural development of the cortex⁵², the visual cortex (inhibitory influence)⁵³
• Differentiation of the cortical neurons of layer IV to II⁵⁴
• Maturation of the motor networks and the spinal cord⁵⁵
• Promotion of neurogenesis in the hippocampus⁵⁶](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751403/))⁵⁷
• Inhibition of neurogenesis in the periventricular hypothalamus and 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. 2020 Sep;38(9):1188-1201. doi: 10.1002/stem.3232. PMID: 32473039.))

4. Noradrenaline - Development - Communication pathways¶

Noradrenaline is produced from a conversion of the amino acid tyrosine, which enters the central nervous system via the bloodstream. Tyrosine is gradually processed into noradrenaline 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 noradrenaline is produced.
Dopamine is converted into noradrenaline by the enzyme dopamine beta-hydroxylase (DBA). The noradrenaline is then stored (like any neurotransmitter) in the synaptic vesicles (storage for neurotransmitters in the nerve endings) until it is activated and released by a nerve impulse.

5. Tonic and phasic noradrenaline¶

We have already explained the basics of tonic and phasic release as well as extracellular levels of a neurotransmitter for dopamine under Tonic / phasic / extracellular dopamine Explained. In the following, we will therefore limit ourselves to the special features of noradrenaline in this regard, based on the presentation by Holland et al.⁵⁸
The interplay between tonic and phasic activity enables adaptive behavior by supporting engagement or disengagement from the task depending on the importance and expected reward or punishment.

5.1. Tonic noradrenaline¶

Tonic noradrenaline activity depends on vigilance (sleep / wakefulness) and external environment (calm / stressful).³⁸
Tonic noradrenergic activity varied during vigilance. During behavioral agitation, LC activity was higher than during goal-directed behavior. Reduced tonic noradrenaline release was associated with sleepiness and a pause in tonic firing a few seconds later was associated with sleep⁵⁹

Tonic and phasic noradrenaline firing are related to each other.
Low tonic activity in unstressed conditions

• enables an adequate, phasic noradrenal infiring of the nucleus coeruleus that is finely tuned to the requirements (stimulus or task).⁶⁰⁶¹³⁷
• globally dampens neuronal responsiveness and is associated with an adaptive narrowing of attention to task-relevant stimuli⁶²
  An increased tonic release of noradrenaline
• increases neuronal responsiveness in the entire cortex⁶²
• causes an expansion of attention to environmental stimuli regardless of their task relevance⁶²
• impaired the ability to distinguish stimuli from distractors. This led to more errors due to increased distractibility or increased signal noise. This in turn reduced participation in the tasks. In rats, stimulation of tonic noradrenal infiring also resulted in increased decision noise and decreased task engagement⁶³
• Increased basal tonic firing in the nucleus coeruleus caused by stress:³⁸
  • an increased state of alertness and an improved ability to recognize unexpected stimuli
  • a more difficult transition to phasic activity, which hinders the ability to focus on a specific goal

5.2. Phasic noradrenaline¶

Phasic noradrenaline activity is triggered by³⁸⁵⁹

• new or unexpected stimuli
• cognitive tasks that require concentration of attention

Phasic noradrenaline activity is driven by the outcome of task-related decision-making processes in the anterior cingulate cortex (ACC) and orbitofrontal cortices (OFC). Phasic adrenaline activity is used to facilitate the behavior resulting from task-related decision-making processes and to optimize task performance. When the utility of a task diminishes, the locus coeruleus exhibits a tonic mode of activity, leading to avoidance of the current task and search for alternative behaviors. Phasic and tonic noradrenaline release thus regulate performance optimization on different time scales.⁶⁴ In more detail Devilbiss, Waterhouse.⁶⁵

In a visual-motor task with reward and punishment, noradrenergic phasic signals followed salient stimuli but not distractions in monkeys. In experiments with poor performance, the noradrenergic phasic response was diminished or nonexistent. Phasic noradrenaline may serve to optimize behavioral responses and vigilance to subsequent sensory stimuli.⁵⁹

When not actively performing tasks, the locus coeruleus returns to a tonic (constant, consistently low) firing rate.⁵⁹

5.3. Tonic and phasic noradrenaline in ADHD and ASD¶

Tonic and phasic noradrenal infiring can be recognized by the pupil diameter.
Here, the basal size of the pupil diameter corresponds to tonic noradrenaline firing and a change in pupil diameter corresponds to phasic noradrenergic activity. A phasic pupil dilation correlated with correct responses, a tonic pupil dilation with periods of low reward value.⁶⁶ An increase in baseline pupil diameter correlated with a decrease in task utility and disengagement from the task (exploration); a decrease in baseline pupil diameter with an increase in task-induced dilation correlated with task engagement (exploitation)⁶⁷
Studies in humans show that pupil diameter also reflects the connectivity between frontoparietal, striatal and thalamic regions of the brain.⁶⁸.

In neurodevelopmental disorders such as ADHD or ASD, the nucleus coeruleus shows basal hyperactivity with higher tonic firing frequency (recognizable by the increased resting-state pupil diameter RSPD), which impairs phasic discharges and consequently the focusing or shifting of attention. The attention deficits in neurodevelopmental disorders are likely to be a consequence of this imbalance³⁸
In Alzheimer’s disease, pupil measurements also showed increased tonic and decreased phasic noradrenaline activity.⁶⁹

5.3.1. Tonic and phasic noradrenaline in ADHD¶

ADHD correlates with an overactivity of the locus coeruleus, especially in the right hemisphere. The kinetics of pupil diameter and reflects the neuronal activity of the locus coeruleus in connection with cognitive functions such as attention and arousal. Temporal patterns of pupil diameter have their own significance. One study found asymmetric pupil diameter, which correlates with the severity of inattention, impulsivity and hyperactivity in ADHD, could be attributed to a left-right imbalance in locus coeruleus activity.⁷⁰

5.3.1.1. Tonic noradrenaline in ADHD¶

In the case of ADHD, on the other hand

• an increased pupil diameter at rest (identical to ASA in this respect)^{7172 72} .
  • Stimulants further increased pupil size⁷³

5.3.1.2. Phasic noradrenaline in ADHD¶

In the case of ADHD

• a reduced (suppressed) pupillary response in an auditory continuous performance task⁷²
• a reduced pupil size in response to an increased amount of stimuli⁷¹
  • Stimulants further reduced pupil dilation⁷³
• reduced change in pupil diameter in response to light stimuli in both eyes and reduced constriction speed of the left eye in ADHD⁷⁴
  • Children with ADHD who responded well to stimulants showed either unusually large or unusually small pupil constrictions to a light stimulus, which tended to normalize when stimulants were taken; non-responders tended to show more consistent values, which changed little with stimulants⁷³
• reduced pupil dilation (as a sign of reduced access to brain capacities) during a resource-intensive task⁷⁵
• unaltered noradrenergic phasic pupil diameter responses⁷⁶ The magnitudes of change in RSPD and EPDR were directly related to each other, supporting the hypothesis of global dysfunction of the LC-NA system.
• increased pupil dilation in response to social stimuli, e.g. happy faces⁷⁷

ADHD and ASD showed differences in visual orienting: an atypical orientation to relatively unexpected targets in ASD and an atypical processing of warning cues in ADHD. The task-related pupil dilation during visual orientation showed:⁷⁸

• shorter latencies of pupil dilation in ADHD compared to ASD, ASD + ADHD and controls
• slower orientation responses to relatively unexpected spatial target stimuli in ASD, which was associated with higher pupil dilation amplitudes compared to people with ADHD and controls

The studies mentioned so far show inconsistent results. So far, no distinction has been made between ADHD presentation forms (subtypes).
One study found a correlation between reduced pupil dilation responses to stimuli and externalizing behaviours 2 years later in children aged 8 to 13 years.⁷⁹ We believe that this may correspond to the reduced cortisol stress response in 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 response⁸⁰ or a flattened error-related negativity (ΔERN)⁸¹⁸² as a predictor or biomarker of externalizing symptoms, e.g. in conduct disorder⁸³

Internalizing disorders, on the other hand, tend to show increased autonomic reactivity and hyperarousal,⁸⁴ e.g. increased error-related negativity (ΔERN) ⁸¹⁸²
Unfortunately, studies on the reactivity of the autonomic nervous system in ADHD do not take into account the differences in the presentation forms (subtypes) of ADHD,⁸⁵ although these are obvious as externalizing and internalizing variants. Consequences of this are that the indifferent results are not surprising for us.

Stimulants increase arousal.⁸⁶ Kleberg et al hypothesize that in ADHD, regardless of existing decreased or increased arousal, stimulants may facilitate response to phasic stimuli by further increasing arousal for people with ADHD. This could explain why stimulants may be beneficial in ADHD-related decreased arousal as well as ADHD-related increased arousal.⁷⁹ This is consistent with a study by the same authors that found that an auditory warning signal (which increases arousal) normalized subsequent performance in people with ADHD⁸⁷

5.3.2. Tonic and phasic noradrenaline in ASA¶

5.3.2.1. Tonic noradrenaline with ASA¶

Children with ASD show a larger pupil diameter at rest (RSPD, a biomarker for increased tonic activity of the nucleus coeruleus) in ASD^{7688 89 90}

5.3.2.2. Phasic noradrenaline with ASA¶

Children with ASD show 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 noradrenaline firing of the nucleus coeruleus^91927893

With ASA, the EPDR was shown in various studies

• increased
  • with visual stimuli⁹³
  • for non-social stimuli^91949588
• reduced
  • with social stimuli⁹¹
  • in an oddball paradigm with three stimuli⁹⁰ The tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptoms.
  • In a visual working memory task, reduced amplitudes of the task-elicited pupil response were found in ASD patients⁶²

In ASD, the adaptation of the pupil to changes in brightness (luminance-adaptation pupillary response, LAPR) is also reduced.⁹¹

The

6. Noradrenaline receptors¶

Noradrenaline receptors are also called adrenoceptors. The three types of noradrenaline receptors are distinguished by their noradrenaline affinity:⁶

• Α1 Adrenoceptors: medium affinity to NA
• Α2 Adrenoceptors: high affinity to NA
• Β Adrenoceptors: low affinity to NA

Noradrenaline works:⁵⁸

• Excitatory via postsynaptic α1- and β-adrenoreceptors
  • Low affinity
  • Only with high noradrenaline levels (acute stress)
• Inhibitory via the primary presynaptic α2-adrenoreceptors
  • Mainly in the PFC
  • High affinity
  • Already addressed at low noradrenaline levels
    (it is currently unclear to us why low noradrenaline levels address the inhibitory autoreceptors; this would already lead to a further reduction in noradrenaline release at low noradrenaline levels; presumably α2-adrenoreceptors do not have an inhibitory effect on noradrenaline release)

6.1. α-1-Adrenoceptors¶

• Postsynaptic
• Medium noradrenaline affinity
  only high noradrenaline levels activate α-1 receptors
• Noradrenaline action at the α-1 receptor:
  • Excitatory by reducing potassium currents.⁹⁶
  • 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. α-1-A adrenoceptor¶

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

6.1.1.2. α-1-B adrenoceptor¶

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

6.1.1.3. α-1-C adrenoceptor (1-D)¶

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

6.1.1.4. α-1-L-adrenoceptor¶

• Open whether own subtype or conformational variant of the alpha 1A receptor
• Agonists:
  * Adrenalin
  * Noradrenaline
  * 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 NA or DA levels⁹⁷
  • Phenylephrine
  • SKF81297 in high concentration
• Shut down PFC⁹⁷⁹⁸
  • Similar model as for cortisol, which controls the “normal” mode of the HPA axis at high-affinity mineralocorticoid receptors and only switches off the HPA axis at the low-affinity glucocorticoid receptors at high cortisol levels, which completely overload the MR

6.1.3. α1-Adrenoceptor antagonists¶

• Improve sustained attention and performance in stop-signal tasks⁹⁹

6.2. α-2 Receptors¶

• Predominantly presynaptic on noradrenaline cells⁵⁸¹⁰⁰
• High noradrenaline affinity
  are therefore also addressed at low noradrenaline levels
• Noradrenaline action at the α-2 receptor: inhibitory by increasing potassium currents¹⁰¹

• α2ARs modulate the inhibitory effect of P neurons.
• α2ARs form receptor heteromers with D4R¹⁰²
  • D4R thereby modulate the inhibitory effect of the P neurons
    • This could explain at least part of the protective effect of D4.4R in ADHD, as well as the increased susceptibility to the development of ADHD mediated by D4.7R.
    • Cortical α2AR-D4.4R heteromers may act as noradrenaline sensors, which are activated at high noradrenaline levels and which then inhibit α2AR activation in the heteromer, which in turn reduces α2AR-mediated inhibition of P neurons.
    • In the α2AR-D4.7R heteromer, the increased potency of noradrenaline 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. α-2-A adrenoceptor¶

• Primarily presynaptic⁵⁸

• High noradrenaline affinity

• Agonists: noradrenaline and dopamine

  • Noradrenaline
    • Increases activity of the PFC
    • Reduces noradrenaline release (autoreceptor = negative feedback)
    • Phasic stimulation in alarm situations¹⁰³
    • Inhibits beta 2 receptors
  • Dopamine
    • Dopamine can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus^104105106

• Widespread throughout the brain¹⁰⁷

  • In PFC and locus coeruleus
  • In the cortex preferentially localized postsynaptically in P neurons of the deep layers¹⁰⁸¹⁰⁹
  • Potentially colocalized with D4R (heteromers)¹⁰²
    • Α2AR-D4R heteromers in significant amounts in the mouse cortex¹¹⁰

• Activation of cortical postsynaptic α2AR showed two opposing neuronal effects:¹⁰²

  • Both dependent on Gi protein-mediated decrease in cAMP formation
  • There are probably two different functional populations of α2AR:
    • Exciting effect
      • Dependent on the inactivation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN)¹¹¹
      • Presumably mediates the therapeutic effect of α2AR agonists by counteracting the cortical frontal hypoactivity of ADHD¹⁰⁸
    • Inhibiting effect
      • Dependent on the inactivation of AMPA receptors¹¹²¹¹³
      • Could be mediated by its own population of α2AR, which represents a protective mechanism in case of overstimulation by high noradrenaline release under stress conditions¹¹²

• Α-2 agonists
  act on presynaptic α-2A receptors: alteration of excitation mechanisms in the basal forebrain and hypothalamus

  • Noradrenaline
  • Dopamine
  • Thyronamine
  • [3H]RX821002¹¹⁴

• Α-2 antagonists have the following effects

  • Improved sustained attention and response inhibition⁹⁹

6.2.1.2. α-2-B-adrenoceptor¶

• Occurs mainly in the thalamus¹⁰⁷
• Sleep regulation
• Α-2 agonists have a sedative / sleep-inducing effect

6.2.1.3. α-2-C adrenoceptor¶

• Widespread throughout the brain¹⁰⁷
  • PFC
  • Locus coeruleus

6.3. β-Adrenoceptors¶

• Postsynaptic
• Low noradrenaline affinity
• Only high noradrenaline levels activate β-receptors
  • Similar model to cortisol, which controls the “normal” mode of the HPA axis at high-affinity mineralocorticoid receptors and only switches off the HPA axis at high levels at the low-affinity glucocorticoid receptors
  • On this side, it is still unclear what is switched off by β-receptors.
  • The activation of microglia by stress appears to be mediated by noradrenaline via β1- and β2-adrenoceptors, but not via β1-adrenoceptors or α-adrenoceptors.¹¹⁵
• Noradrenaline action at the β-receptor: excitatory by reducing potassium currents.⁹⁶
• Β-antagonists (beta-blockers)
  • Improve sustained attention and performance in stop-signal tasks (SST).⁹⁹
  • Increase impulsivity in healthy subjects⁵⁸

6.3.1. β-1-Adrenoceptor¶

• In the heart, kidneys, fatty tissue and other tissues
• Higher affinity for adrenaline than for noradrenaline
• CAMP control loop
  • Beta 1 increases cAMP synthesis
  • High cAMP phosphorylates serine and threonine residues of the beta 1 receptor, which desensitizes it
• Increase in cardiac strength and frequency
• Lipolysis
• Increased release of renin
  • → Stimulation of the renin-angiotensin-aldosterone system
  • → Increase in peripheral blood pressure
• Β1-agonists
  • Adrenalin
  • Isoprenaline (isoproterenol)
  • Noradrenaline
  • Xamoterol
  • Denopamine
• Β1 antagonists
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propanolol
  • Metoprolol
  • Bisoprolol
  • Atenolol
  • Betaxolol

6.3.2. β-2-Adrenoceptor¶

• Relaxation of the smooth muscles in the bronchi, uterus, blood vessels and intestines
• Often found in the hippocampus in the brain¹¹⁶
  • A β2 receptor gene variant prolongs NA binding and is more frequently observed in PTSD¹¹⁶
• Β2-agonists
  • Adrenalin
  • Isoprenaline (isoproterenol)
  • Noradrenaline
  • Salbutamol
  • Salmeterol
  • Clenbuterol
  • Terbutaline
  • Formoterol
  • Fenoterol
• Β2 antagonists
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propanolol
  • ICI 118551

6.3.3. β-3-Adrenoceptor¶

• Lipolysis and thermogenesis in brown adipose tissue
• Β3 agonists
  • Adrenalin
  • Isoprenaline (isoproterenol)
  • Noradrenaline
  • Amibegron
  • Mirabegron
  • Solabegron
• Antagonists
  • Alpha-2 receptors in the locus coeruleus (autoinhibition)
  • Propanolol
  • SR59230A

6.3.4. β-4-Adrenoceptor¶

• It is unclear whether an independent type of beta 4 receptor exists or whether it is an affinity state of the beta 1 receptor

6.4. Noradrenaline also addresses dopamine D2-type receptors (D2, D3, D4)¶

Noradrenaline also binds to D2-type receptors with different affinities: D3R > D4R ≥ D2SR ≥ D2LR.¹¹⁷
Dopamine, in turn, can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus.^104105106

7. Reuptake and breakdown of noradrenaline¶

7.1. (Re)uptake of noradrenaline¶

7.1.1. Noradrenaline transporter (NET)¶

Noradrenaline transporters (like all transporters) are always located at the presynapse and take neurotransmitters back into the cell. Noradrenaline transporters are always found on noradrenergic cells.
In addition to noradrenaline, the noradrenaline transporter also reabsorbs dopamine. The noradrenaline transporter appears to be reduced in the attention networks of the right hemisphere of the brain in ADHD.¹¹⁸

7.1.2. Plasma membrane monoamine transporter (PMAT)¶

Although considerably weaker than dopamine, noradrenaline continues to be taken up by the plasma membrane monoamine transporter (PMAT). This is also known as human equilibrative nucleoside transporter-4 (hENT4). It is encoded by the gene SLC29A4. 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, noradrenaline, adrenaline and histamine.¹¹⁹

7.1.3. Organic cation transporters (OCT)¶

Noradrenaline (and to a lesser extent dopamine) is taken up from the extracellular area to a lesser extent by the organic cation transporters (OCT1, OCT2, OCT3). These are also referred to as solute carrier family 22 members 1/2/3 or extraneuronal monoamine transporters (EMT). OTC2 and OTC3 are found in nerve cells and astrocytes and bind histamine > noradrenaline and adrenaline > dopamine > serotonin.¹¹⁹ Uptake does not take place in the presynaptic cell as with DAT and NET, but in glial cells. There, dopamine and noradrenaline are degraded by COMT to methoxytyramine.¹²⁰
OCT3 appears to occur mainly peripherally and barely in the brain.¹¹⁹

The coding genes are:¹²¹

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

Antagonists of OCT are e.g.¹²⁰

• Amantadine
• Memantine

7.2. Noradrenaline degradation through metabolization¶

While noradrenaline transporters and dopamine transporters cause the reuptake of noradrenaline from the synaptic cleft back into the sending cell, where they are stored in vesicles again by VMAT2 transporters, dopamine is also broken down by conversion into other substances. COMT and MAO-B are the most important of these.

7.2.1. PFC: Noradrenaline degradation by COMT¶

In the PFC in particular, noradrenaline is degraded by the enzyme catechol-O-methyltransferase (COMT) in addition to being reabsorbed by NET.

For details, see =&gt Dopamine degradation through COMT in the article =&gt Dopamine reuptake and degradation.

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

For details, see =&gt Dopamine degradation through COMT in the article =&gt Dopamine reuptake and degradation.

7.2.1.2. Estrogen reduces dopamine degradation by COMT in the PFC¶

For details, see =&gt Dopamine degradation through COMT in the article =&gt Dopamine reuptake and degradation.

7.2.2. Noradrenaline degradation by monoamine oxidase (MAO-A)¶

Noradrenaline (as well as adrenaline) continues to be broken down by MAO-A. Dopamine, on the other hand, is broken down by MAO-B.¹²⁰

7.3. Noradrenaline degradation through diffusion¶

In the DAT-KO mouse, inhibition of serotonin transporters, noradrenaline 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 appears to occur more by diffusion.¹²² This is probably also true for noradrenaline.

8. Regulation of noradrenaline¶

8.1. Mental and physical activity¶

Noradrenaline and adrenaline levels are increased by mental activity as well as physical activity.

• Noradrenaline and adrenaline are also elevated in the case of unpleasantly underchallenging activities, but far more so in the case of activities that are perceived as equally unpleasantly overchallenging.
• In a boring, under-stimulating task, test subjects with higher adrenaline levels performed better than those with lower adrenaline levels. In contrast, subjects with lower adrenaline levels performed better in a challenging, overstimulating task.⁴
• Optimal noradrenaline signaling is linked to a certain level of noradrenaline. Too little noradrenaline, like too much noradrenaline, impairs noradrenergic signaling.⁵⁸ This corresponds to the well-known inverted-U model, which also applies to dopamine and serotonin.
• By influencing the ARAS, noradrenaline is linked to different increments of arousal.
  The level of arousal (excitement) helps to control behavior. Too little (underactivation) and too much arousal (stress) impairs performance. Individuals therefore strive for the optimal level of arousal for them. This arousal is noradrenergically regulated.⁷
  More on the mechanisms of activation (ARAS etc.): ⇒ Activation from a neurological perspective

8.2. Stress¶

Electrical shocks increase the release of adrenaline and noradrenaline, and the less control the person with ADHD has over this, the greater the increase. Various stressful events increase noradrenaline release, particularly in the hypothalamus, amygdala and locus coeruleus.¹²³ This explains why an increased release of noradrenaline is associated with the provocation of negative emotions such as anxiety and/or fear.¹²⁴

A high adrenaline level correlates with faster decisions and fewer errors in cognitive tests, while a lower adrenaline level correlates with slower decisions and higher error rates.⁴

Cortisol exerts an inhibitory influence not only on the HPA axis, but also on the locus coeruleus and thus on the release of noradrenaline in the CNS (negative feedback). If this inhibition is restricted (due to hypocortisolism), the person with ADHD lacks an important “stress brake”.¹²⁵
As with dopamine, it is not just the presence or absence of the neurotransmitter noradrenaline that is important, but 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.
Increased tonic noradrenaline activity, on the other hand, leads to poorer performance.¹⁶
Clonidine is said to be able to improve phasic noradrenaline activity in the locus coeruleus.¹⁶ This should therefore also apply to guanfacine.

8.3. Fever¶

Fever affects the noradrenergic system.
It has been reported that some people with ADHD have fewer or no autistic symptoms when they have a fever.³⁵ ASD symptoms are also noradrenergically mediated, among other things.

9. Treatment options for noradrenergic disorders¶

9.1. Medication¶

Noradrenaline reuptake inhibitors increase the availability of noradrenaline in the synaptic cleft by inhibiting the problematic overactivity of noradrenaline reuptake transporters (e.g. in ADHD).
Stimulants (amphetamine drugs, MPH and atomoxetine) act as dopamine reuptake inhibitors and also cause increased production of dopamine and noradrenaline and, to a lesser extent, serotonin.
Stimulants have dopaminergic effects on the nucleus accumbens and improve symptoms of hyperactivity and self-activation/reinforcement processes, while response delay and working memory problems are mediated by noradrenergic effects of the locus coeruleus on the PFC. Effects of stimulants on attention and behavioral control are dopaminergic and noradrenergic mediated.¹²⁶
While norepinephrine, like dopamine, is decreased in the PFC in ADHD, norepinephrine is increased in the PFC in PTSD, which (above a certain level) deactivates the PFC and activates the amygdala, which is why PTSD is typically treated with alpha-1 or beta-adrenoceptor antagonists, which counteract the shutdown of the PFC by too much norepinephrine.¹⁰⁷
Korsakoff’s syndrome is a disorder with a pronounced persistent impairment of short and long-term memory (amnestic disorder) due to thiamine deficiency, which usually occurs as a consequence of chronic alcohol consumption. In Korsakoff’s disease, the levels of the noradrenaline degradation product MHPG in the cerebrospinal fluid are reduced, which correlates with an impairment of short-term memory. The alpha-2 receptor agonist clonidine improves the memory and attention deficits in Korsakoff’s, while it worsens them in healthy individuals.¹²⁷

9.2. Non-drug treatment¶

9.2.1. Structured daily routine (i.e. break rhythm)¶

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

The ability of the locus coeruleus to control activation should be trainable through a clear daily rhythm with appropriate breaks (not forced, but sensibly self-set, but also consistently carried out).⁷

10. Disorders of the noradrenaline system¶

10.1. Noradrenaline in ADHD¶

Noradrenaline has the second greatest influence on ADHD after dopamine.

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

Only the ADHD symptom of a lack of inhibition of executive functions is mediated dopaminergically by the striatum, while the lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.¹²⁸ Therefore, only the former is amenable to dopaminergic treatment.
Emotion regulation and affect control, on the other hand, are better treated noradrenergically.

The amount of noradrenaline metabolites (NE degradation products) in the urine normalizes with and further after puberty, parallel to the decrease in (child-typical) ADHD-HI symptoms. This could be an indication of a brain maturation delay in ADHD.¹²⁹
This type of brain maturation delay is found more frequently than average in carriers of the DRD4 7R polymorphism¹³⁰ Whether it is a pathological brain maturation delay or the prolonged brain maturation typical of more gifted people (⇒ ADHD) Giftedness and ADHD) is an open question. High sensitivity is associated with the DRD4 7R polymorphism as a risk/opportunity gene. More on this at ⇒ How ADHD develops: genes + environment.

The noradrenaline transporter, which also absorbs dopamine, appears to be reduced in the attention networks of the right hemisphere of the brain in ADHD.¹¹⁸

One study replicated other studies showing that children with ASD have increased tonic (resting pupil diameter) and decreased phasic (PDR and ERP) activity of the nucleus coreuleus-norepinephrine system. The tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptoms.⁹⁰

10.2. Noradrenaline with ASA¶

See above under Tonic noradrenaline in ASA and Phasic noradrenaline in ASA.