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Norepinephrine

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Norepinephrine

1. Adrenaline and noradrenaline in the body (hormone)

For an overview, see Hässler, Irmisch.1

Adrenaline and noradrenaline (also called norephinephrine, NE) are (like dopamine) biogenic amines and catecholamines. They are continuously produced and metabolized in the body and are always present in small amounts in the arterial blood.

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

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

In the body, norepinephrine is generated primarily in sympathetic nerve endings and, in addition, in small amounts in the adrenal medulla. Norepinephrine basically has a vasoconstructive effect (except on the coronary vessels) and increases both systolic and diastolic blood pressure.

Norepinephrine and epinephrine promote oxygen turnover, activate fat breakdown, and increase free fatty acids (FFS) in plasma.2

2. Norepinephrine in the brain (neurotransmitter)

2.1. Control ranges of norepinephrine

The different noradrenaline affinity of adrenoceptors controls different phases of activity:3

  • Sleep: norepinephrine level at zero
  • Quiet wakefulness: α2-receptors are activated
  • Active wakefulness, physical stress: α2- and α1-receptors are activated
  • Stress: α2-, α1-, and β-receptors are activated.

Norepinephrine regulates:

  • Attention
    Norepinephrine acts on the posterior center of attention.4
    When the neurotoxin DSP-4 destroys the norepinephrine receptors in animals, they develop increased distractibility.5
    Norepinephrine modulates attention in 2 ways
  • Vigilance8
  • Activity i.e. general behavioral activation9
  • Working memory8
  • Motivation10
  • Stimulus perception11
  • Influencing the ascending reticular attentional system (ARAS, ascending reticular activating system)8
  • Pulse control10
  • Inhibition12
  • Mood10
    • Norepinephrine limits mood swings10
  • Memory
    • For feelings10
    • For aversive memory contents7
  • Executive functions13
  • Increases risk appetite14
  • Makes more uncritical14
  • Increases alertness, reduces fatigue14
  • Increases sex drive14
  • Increases sense of self-worth14
  • Reduces appetite14
  • Is involved in stress symptoms6
    • Sympathomimetic14
      • Dilates bronchi (bronchial dilatation)
      • Increases blood pressure
    • In (generalized) anxiety disorder and PTSD, norepinephrine levels are elevated in the autonomic nervous system (here: sympathetic nervous system).1516
      • Norepinephrine agonists (e.g., yohimbine) enhance the anxiety (and stress) response9
    • Norepinephrine is closely associated with the endocrine stress systems, especially CRH and ACTH systems there9(Vegetatives Nervensystem, HPA-Achse)
    • Norepinephrine affects CRH output in the hypothalamus (HPA axis) via noradrenergic alpha1 receptors common there, while CRH from the hypothalamus in turn (like stressors themselves) increases norepinephrine output in the locus coeruleus, which is released into the PFC.17
      • Endogenous opioids attenuate not only pain but also the noradrenergic stress response mediated by CRH18
    • The locus coeruleus (the site of origin of norepinephrine) indirectly addresses the sympathetic nervous system.18
      • By norepinephrine from there influencing neurons in the medulla oblongata, which in turn excite preganglionic neurons.18
    • Acute stress increases the noradrenaline level19
      • Amygdala and PFC (relevant for emotional experience).19Permanent stress leads to permanently elevated norepinephrine levels and consequently to a downregulation of the corresponding adrenoceptors (norepinephrine receptors) in
        • Periaqueductal gray (relevant for behavior control)19
        • Hypothalamus19
        • Dorsomedial medulla oblongata (medulla; relevant for control of autonomic functions)19
      • In contrast, Rensing et al, citing the aforementioned sources, report upregulation of norepinephrine receptors in the limbic system20
        Downregulation and upregulation are not necessarily mutually exclusive, but can arise sequentially at different phases of a stress response according to the norepinephrine receptor hypothesis.
        According to this, upregulation would be typical for the final state of depression, whereas downregulation corresponds to the first step (see Phases of stress development).
        Norepinephrine receptor hypothesis of depression
      • Downregulation is a general response to neurotransmitter levels that have been too high for too long and leads to desensitization of the respective receptors, with first the postsynaptic receptors and then the presynaptic autoreceptors (releasing the neurotransmitter) decreasing. This disrupts the release inhibition of the neurotransmitter. This is followed by a permanent overactivity of the neurotransmitter neurons (resistance phase). If the stress situation continues, neurotransmitter production in the neurons collapses (exhaustion phase). As a result of this, the receptors regulate themselves up again.
        To downregulation and upregulation Stress damage due to early childhood or prolonged stress.
        On the phases of a stress response: ADHD as a chronicized stress regulation disorder.
    • Norepinephrine (along with CRH and vasopressin) influences ACTH output in the pituitary gland (HPA axis). ACTH is decreased by stimulation of noradrenergic alpha2 receptors and increased by stimulation of noradrenergic beta receptors.9
  • Endogenous opioids may reduce the noradrenaline-stimulating effect of CRH in the nucleus coeruleus.21
  • Norepinephrine increases vasopressin output.22
  • Norepinephrine is not released in the brain during sleep.23

2.2. Norepinephrine level

  • In acute stress, target neurons are only temporarily exposed to high concentrations of norepinephrine; in chronic stress, they are permanently exposed
    • Electrical shocks increase adrenaline and noradrenaline output, and the less control the subject has over this, the more so.
  • Norepinephrine and epinephrine levels are increased by mental activity as well as by physical activity
    • Norepinephrine and epinephrine are also elevated in unpleasantly underdemanding activity, but far more so in overdemanding activity perceived as equally unpleasant.
    • In a boring, understimulating task, subjects with higher adrenaline levels performed better than those with lower adrenaline levels. In a demanding, overstimulating task, on the other hand, subjects with lower adrenaline levels performed better.2
    • By affecting the ARAS, norepinephrine is linked to different levels of arousal.
      The level of arousal (arousal) helps to control behavior. Too little arousal (underactivation) and too much arousal (stress) impairs performance. Individuals therefore strive for the optimal level of arousal for them. This arousal is regulated noradrenergically.23
      More on the mechanisms of activation (ARAS et al): Activation from a neurological point of view

Individual arousal

This is the reason why some people constantly need a radio or music in the background (arousal-increasing) to maintain their performance, possibly even to reach the “general arousal state” in the first place in order to be able to learn, while others avoid any additional stimulus in order to move from their too high arousal level towards the optimum. The arousal level is an inverted U - the middle is the optimum, too much as well as too little is detrimental to performance. Important: each person can only judge for himself what is the right level for him. Some people need a basic activity instead of a basic acoustic stimulation. We know quite a few affected people who can concentrate much better if they knit at the same time. It is conceivable that hyperactivity i.e. fidgetiness could be co-triggered by too little tactile basic excitation. It is a fact that fidgeting reduces stress.

  • High adrenaline correlates with faster decisions, fewer errors in cognitive tests, and decreased adrenaline correlates with slower decisions and higher error rates.2

2.3. Norepinephrine in ADHD

Norepinephrine has the second largest influence in ADHD after dopamine.

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

Only the ADHD symptom of lack of inhibition of executive functions is dopaminergically mediated by the striatum, whereas the lack of inhibition of emotion regulation is noradenergically caused by the hippocampus.24 Therefore, only the former would be amenable to dopaminergic treatment.
Emotion regulation and affect control, on the other hand, are better treated noradrenergically.

The amount of norepinephrine metabolites (NE breakdown products) in urine normalizes with and further after puberty, in parallel with the decrease of (child-typical) ADHD-HI symptoms. This may indicate a brain maturation delay in ADHD.25
Such a brain maturation delay is found with above-average frequency in carriers of the DRD4 7R polymorphism26 Whether it is a pathological brain maturation delay or the prolonged brain maturation typical of more gifted people (Giftedness and ADHD) is an open question. High sensitivity is associated with the DRD4 7R polymorphism as a risk/chance gene. For more on this, see How ADHD develops: Genes + Environment.

The norepinephrine transporter, which also picks up dopamine, appears to be reduced in ADHD in right hemisphere attentional networks.27

3. Noradrenergic communication of the brain

The brain contains several communication systems by means of which certain brain areas 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 information exchange using noradrenaline (noradrenergic pathways).

3.1. Cortical norepinephrine pathway of the nucleus coeruleus

Source28

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

Norepinephrine release in the locus coeruleus is controlled by arousal.29

  • Sleep
    • REM sleep
      • No noradrenaline release
    • Slow-wave sleep
      • Tonic: little release of noradrenaline
  • For low arousal (sleepiness)
    • Tonic: little release of noradrenaline
    • Phasic: little noradrenaline release
  • Response to relevant stimuli in unstressed waking state
    • Tonic: moderate
    • Phasic: distinct
  • With stress
    • Tonic: strong
    • Phasic: little to dysregulated

Phasic norepinephrine activity is controlled by the outcome of task-related decision processes in anterior cingulate cortex (ACC) and orbitofrontal cortices (OFC). Phasic epinephrine activity is used to facilitate the behavior resulting from task-related decision processes and to optimize task performance.
If the utility of a task diminishes, the nucleus coeruelus exhibits a tonic mode of activity, leading to aversion from the current task and a search for alternative behaviors. Phasic and tonic norepinephrine release thus regulate performance optimization on different time scales.30 In depth Devilbiss, Waterhouse.31

3.2. Cortical-tegmental norepinephrine pathway

Source28

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

3.3. Interaction cortisol - locus coeruleus

Cortisol exerts an inhibitory influence not only on the HPA axis, but also on the locus coeruleus and thus on norepinephrine release in the CNS (negative feedback). If this inhibition is limited (by hypocortisolism), the affected person lacks an important “stress brake”.32
As with dopamine, it is not the presence or absence of the neurotransmitter norepinephrine alone that matters, but a distinction must be made between phasic (short-term) and tonic (long-term) presence.
Increased phasic activity in the nucleus coeruleus causes good attention.
In contrast, increased tonic norepinephrine activity leads to poorer performance.6
Clonidine is thought to be capable of enhancing phasic norepinephrine activity in the nucleus coeruleus.6 This should therefore also apply to guanfacine.

4. Norepinephrine - formation - communication pathways

Norepinephrine is formed from a conversion of the amino acid tyrosine, which enters the central nervous system via the bloodstream. Tyrosine is gradually converted to 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 stored (like any neurotransmitter) in the synaptic vesicles (stores for neurotransmitters in the nerve endings) until it is activated by a nerve impulse.

The action of norepinephrine is terminated by two enzymes that convert norepinephrine to an active metabolite.
The first is monoamine oxidase (MAO) A or B, the other is catechol-O-methyl transferase (COMT).
The restriction of the effect of norepinephrine can also be caused by too many / too active norepinephrine transporters, which leads to too low a norepinephrine level in the synaptic cleft via increased reuptake, without the norepinephrine being destroyed as a result.

5. Norepinephrine release

The basic differences of tonic and phasic release can be found at =&gt Tonic dopamine / phasic dopamine In the article =&gt Dopamine.

6. Receptors

6.1. Postsynaptic norepinephrine receptors

Norepinephrine receptors are also called adrenoceptors. The three norepinephrine receptor types are distinguished on the basis of norepinephrine affinity:3

  • Α1 adrenoceptors: medium affinity for NA
  • Α2 adrenoceptors: high affinity for NA
  • Β Adrenoceptors: low affinity for NA

6.1.1. Noradrenergic α-1 receptors

  • Medium norepinephrine affinity
    only high norepinephrine levels activate α-1 receptors
  • Norepinephrine action at the α-1 receptor
    • Excitatory by reducing potassium currents.33
    • Activation of phospholipase C
      • → Formation of inositol trisphosphate (IP3) (second messenger)
      • → Formation of diacylglycerol (DAG) (second messenger)
  • Alpha 1 receptor types
    • Alpha 1A
      • Agonists
        • Adrenalin
        • Norepinephrine
        • Phenylephrine
        • A-61603
        • Oxymetazoline
      • Antagonists
        • Prazosin
        • Doxazosin
        • Terazosin
        • Alfuzosin
        • Urapidil
        • Sertraline
        • Tamsulosin
        • 5-Methylurapidil
        • B8805-033
        • SNAP 5089
        • RS-17053
    • Alpha 1B
      • Agonists
        • Adrenalin
        • Norepinephrine
        • Phenylephrine
      • Antagonists
        • Prazosin
        • Doxazosin
        • Terazosin
        • Alfuzosin
        • Urapidil
        • Sertraline
        • Tamsulosin
        • Chloroethylclonidine
        • L-765314
    • Alpha 1C (1D)
      • Agonists
        • Adrenalin
        • Norepinephrine
        • Phenylephrine
        • Buspiron
      • Antagonists
        • Prazosin
        • Doxazosin
        • Terazosin
        • Alfuzosin
        • Urapidil
        • Sertraline
        • Tamsulosin
        • BMY 7378
        • MDL 73005EF
    • Alpha 1L
      • Open, whether own subtype or conformational variant of the alpha 1A receptor
      • Agonists
        • Adrenalin
        • Norepinephrine
        • Phenylephrine
        • A-61603
        • Antagonists
          • Prazosin
          • Doxazosin
          • Terazosin
          • Alfuzosin
          • Urapidil
          • Sertraline
          • Tamsulosin
  • Α1-receptor agonists
    • Can mimic the effects of high NA or DA levels34
      • Phenylephrine
      • SKF81297 in high concentration
    • Shut down PFC3435
      • Similar model to cortisol, which controls “normal” mode at high-affinity mineralocorticoid receptors and shuts down the HPA axis at low-affinity glucocorticoid receptors only when cortisol levels are high and completely exhaust the MR
  • Α1-receptor antagonists
    • Improve sustained attention and performance in stop-signal tasks36

5.1.2. Noradrenergic α-2 receptors

  • Predominantly postsynaptic to norepinephrine cells
  • High norepinephrine affinity
    are therefore also addressed at low norepinephrine levels
  • Norepinephrine action at the α-2 receptor: inhibitory by increasing potassium currents37
  • Α-2 receptor types
    • Type alpha 2A: in PFC and nucleus coeruleus
      • Norepinephrine
        • Increases activity of the PFC
        • Decreases noradrenaline release (autoreceptor = negative feedback)
        • Phasic stimulation in alarm situations38
          this reactivity designed for phasic stimulation could be the reason why a permanent (tonic) increase of the noradrenaline level by noradrenergic drugs does not cause a permanent improvement of the cognitive abilities of the PFC, precisely because they are designed for phasic stimulation and downregulate during tonic stimulation. This could explain the common experience why noradrenergic drugs initially work very well but soon lose this effect.
        • Inhibits beta 2 - receptors
      • Dopamine
        • Dopamine can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus394041
      • Α-2 agonists
        • Thyronamine
        • [3H]RX82100242
        • Act at presynaptic α-2A receptors: alteration of excitatory mechanisms in the basal forebrain and hypothalamus
      • Α-2 antagonists cause
        • Improved sustained attention and response inhibition36
    • Type Alpha 2B
      • In the thalamus
        • Sleep regulation
      • Α-2-agonists act
        • Sedative / sleep-inducing
    • Type Alpha 2C
      • PFC
      • Nucleus coeruleus

6.1.3. Noradrenergic β-receptors

  • Low norepinephrine affinity
  • Only high norepinephrine levels activate β-receptors
    • Similar model to cortisol, which controls “normal” mode at high-affinity mineralocorticoid receptors and shuts down HPA axis only at high levels at low-affinity glucocorticoid receptors
    • On this side, it is still unclear what is switched off by β-receptors.
    • Activation of microglia by stress appears to be mediated by norepinephrine via β1- and β2-adrenoceptors but not via β1-adrenoceptors or α-adrenoceptors.43
  • Norepinephrine action at the β-receptor: excitatory, reducing potassium currents.33
  • Β-Antagonists
    • Cause improved sustained attention and performance in stop-signal tasks (SST).36
  • Β-receptor types
    • Beta 1
      • In heart, kidney, adipose tissue and other tissues
      • Higher affinity to adrenaline than to 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 of 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)
        • Norepinephrine
        • Xamoterol
        • Denopamine
      • Β1-antagonists
        • Alpha-2 receptors in the locus coeruleus (autoinhibiton)
        • Propanolol
        • Metoprolol
        • Bisoprolol
        • Atenolol
        • Betaxolol
    • Beta 2
      • Relaxation of smooth muscles in bronchi, uterus, blood vessels, intestines
      • Β2-agonists
        • Adrenalin
        • Isoprenaline (isoproterenol)
        • Norepinephrine
        • Salbutamol
        • Salmeterol
        • Clenbuterol
        • Terbutaline
        • Formoterol
        • Fenoterol
      • Β2-antagonists
        • Alpha-2 receptors in the locus coeruleus (autoinhibiton)
        • Propanolol
        • ICI 118551
    • Beta 3
      • Lipolysis and thermogenesis in brown adipose tissue
      • Β3-agonists
        • Adrenalin
        • Isoprenaline (isoproterenol)
        • Norepinephrine
        • Amibegron
        • Mirabegron
        • Solabegron
      • Antagonists
        • Alpha-2 receptors in the locus coeruleus (autoinhibiton)
        • Propanolol
        • SR59230A
    • Beta 4
      • Unclear whether an independent beta 4 receptor type exists or whether it is an affinity state of the beta 1 receptor

6.2. Presynaptic norepinephrine autoreceptors

These are always alpha 2 receptors.44 Autoreceptors serve to regulate (inhibit) their own release (here: of noradrenaline).

6.3. Norepinephrine also addresses dopamine D2-type receptors (D2, D3, D4)

Norepinephrine simultaneously binds to D2-type receptors with different affinities: D3R > D4R ≥ D2SR ≥ D2L.45
Dopamine, in turn, can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus.394041

7. Norepinephrine degradation

7.1. (Re)uptake of norepinephrine

7.1.1. Norepinephrine transporter (NET)

Noradrenaline transporters (like DAT) are always located at the presynapse.

The noradrenaline transporter also takes up dopamine. The norepinephrine transporter appears to be reduced in ADHD in the attention networks of the right cerebral hemisphere.27

7.1.2. Plasma membrane monoamine transporter (PMAT)

Norepinephrine - although considerably weaker than dopamine - is further 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 high-affinity dopamine and serotonin and, much more weakly, norepinephrine, epinephrine, and histamine.46

7.1.3. Organic Cation Transporters (OCT)

Norepinephrine (weaker also dopamine) is further 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 member 1/2/3 or extraneuronal monoamine transporters (EMT). OTC2 and OTC3 are found in neurons and astrocytes and bind histamine > norepinephrine and epinephrine > dopamine > serotonin.46 Uptake does not occur in the presynaptic cell as in DAT and NET, but in glial cells. There, dopamine and norepinephrine are degraded by COMT to methoxytyramine.47
OCT3 appears to occur mainly peripherally and rarely in the brain.46

The coding genes are:48

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

Antagonists of OCT are, for example.47

  • Amantadine
  • Memantine

7.2. Norepinephrine degradation by metabolization

While norepinephrine transporters and dopamine transporters cause the reuptake of norepinephrine from the synaptic cleft back into the transmitting cell, where it is reincorporated into vesicles by VMAT2 transporters, dopamine is also degraded by conversion into other substances. COMT and MAO-B are the main ones to be mentioned here.

7.2.1. PFC: Norepinephrine degradation by COMT

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

For details, see =&gt Dopamine degradation by COMT in the article =&gt Dopamine.

7.2.1.1. COMT gene variants alter norepinephrine levels in the PFC

For details, see =&gt Dopamine degradation by COMT in the article =&gt Dopamine.

7.2.1.2. Estrogen reduces dopamine degradation by COMT in the PFC

For details, see =&gt Dopamine degradation by COMT in the article =&gt Dopamine.

7.2.2. Norepinephrine degradation by monoamine oxidase (MAO-A)

Norepinephrine (as well as epinephrine) continues to be degraded by MAO-A. Dopamine, on the other hand, is degraded by MAO-B.47

7.3. Norepinephrine depletion 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. This seems to occur more by diffusion in the absence of DAT in the striatum.49 This should also be true for norepinephrine.

8. Treatment options for noradrenergic disorders

8.1. Medication

Norepinephrine reuptake inhibitors increase the availability of norepinephrine in the synaptic cleft by inhibiting the overactivity of norepinephrine reuptake transporters that is problematic (e.g., in ADHD).
Stimulants (amphetamine drugs, MPH, and atomoxetine) act as dopamine reuptake inhibitors and also cause increased production of dopamine and norepinephrine and, to a lesser extent, serotonin.
Stimulants act dopaminergically on the nucleus accumbens to improve symptoms of hyperactivity and self-activation/reinforcement processes, whereas 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 mediated dopaminergically and noradrenergically.50

8.2. Non-drug treatment

8.2.1. Structured daily routine (i.e. rhythm of breaks)

The noradrenergic system of the brain is completely deactivated during sleep. Upon waking, it is activated by the nucleus coeruleus.

The ability of the nucleus coeruleus to control activation should be trainable by a clear daily rhythm with appropriate breaks (not imposed, but sensibly self-set, but also consistently performed).23


  1. Hässler, Irmisch: Biochemische Störungen bei Kindern mit AD(H)S, Seite 87, in Steinhausen (Hrsg.) (2000): Hyperkinetische Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Kohlhammer, Seite 89

  2. Frankenhaeuser (1971): Behavior and circulating catecholamines. Brain Research, 31(2), 241-262. http://dx.doi.org/10.1016/0006-8993(71)90180-6

  3. Atzori, Cuevas-Olguin, Esquivel-Rendon, Garcia-Oscos, Salgado-Delgado, Saderi, Miranda-Morales, Treviño, Pineda, Salgado (2016): Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation? Front Synaptic Neurosci. 2016 Aug 26;8:25. doi: 10.3389/fnsyn.2016.00025. eCollection 2016.

  4. http://www.adhs.org/genese/

  5. Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 215

  6. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, Seite 85

  7. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 86 mit weiteren Nachweisen

  8. Graf (2009): Modulation kognitiver Funktionen durch die Einnahme einer Einmaldosis des Noradrenalin- Wiederaufnahmehemmers Atomoxetin bei gesunden freiwilligen Probanden: eine randomisierte, placebo-kontrollierte Studie mittels funktioneller Magnetresonanztomographie, Dissertation; Achtung, Untersuchung zu Atomoxetin mit geringer Probandenzahl von n = 12; Einmalgabe von Atomoxetin per se unsinnig; theoretischer Teil dagegen lesenswert

  9. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 86

  10. Simchen, Helga: http://helga-simchen.info/Thesen-zu-ADS; dort: was bewirken die Botenstoffe?

  11. Oades, Röpcke (2000).: Neurobiologische Grundlagen der Aufmerksamkeit: „Über die Freiheit der Wahl“. Sprache – Stimme – Gehör 24 (2000) 49 – 56

  12. Aston-Jones, Gold (2009): How We Say No: Norepinephrine, Inferior Frontal Gyrus, and Response Inhibition; Biol Psychiatry. 2009 Apr 1; 65(7): 548–549.; doi: 10.1016/j.biopsych.2009.01.022; PMCID: PMC2777813; NIHMSID: NIHMS141636

  13. Graf (2009): Modulation kognitiver Funktionen durch die Einnahme einer Einmaldosis des Noradrenalin- Wiederaufnahmehemmers Atomoxetin bei gesunden freiwilligen Probanden: eine randomisierte, placebo-kontrollierte Studie mittels funktioneller Magnetresonanztomographie, Dissertation; Hinweis: Untersuchung zu Atomoxetin mit geringer Probandenzahl von n = 12; Einmalgabe von Atomoxetin ist per se unsinnig; theoretischer Teil dagegen lesenswert

  14. Mang (2018): 05. Monoamine 2: Amphetamin, Ritalin (ADHS), Cocain, Tricyclika, Videovorlesung. ca. bei Minute 30.

  15. Klein, Corwin (2002): Seeing the unexpected: how sex differences in stress responses may provide a new perspective on the manifestation of psychiatric disorders. Curr Psychiatry Rep. 2002 Dec;4(6):441-8.

  16. Geracioti, Baker, Ekhator, West, Hill, Bruce, Schmidt, Rounds-Kugler, Yehuda, Keck, Kasckow (2001): CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder; American Journal of Psychiatry 2001 158:8, 1227-1230

  17. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seiten 86, 87

  18. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 87

  19. Fuchs und Flügge (2004): Psychosozialer Stress verändert das Gehirn, Neuroforum 2/04, 195

  20. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 74

  21. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle; Elsevier Spektrum (heute: Springer), Kapitel 4, neurobiologische Grundlagen von Stressreaktionen, Seite 87

  22. Willoughby, Jervois, Menadue, Blessing (1987): Noradrenaline, by Activation of Alpha-1-Adrenoceptors in the Region of the Supraoptic Nucleus, Causes Secretion of Vasopressin in the Unanaesthetized Rat. Neuroendocrinology 1987;45:219-226. doi: 10.1159/000124729

  23. Müller, Candrian, Kropotov (2011): ADHS – Neurodiagnostik in der Praxis, Springer, Seite 86

  24. Müller, Candrian, Kropotov (2011): ADHS – Neurodiagnostik in der Praxis, Springer, Seite 85

  25. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, Seite 85

  26. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, S. 79

  27. Ulke, Rullmann, Huang, Luthardt, Becker, Patt, Meyer, Tiepolt, Hesse, Sabri, Strauß (2019): Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study. Transl Psychiatry. 2019 Nov 15;9(1):301. doi: 10.1038/s41398-019-0619-y.

  28. Helmchen, Henn, Lauter, Sartorius (2013): Psychiatrie der Gegenwart 1: Grundlagen der Psychiatrie, Springer, Seite 190

  29. Aston-Jones, Rajkowski, Cohen (1999): Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry. 1999 Nov 1;46(9):1309-20.

  30. Aston-Jones, Cohen (2005): Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005 Dec 5;493(1):99-110.

  31. Devilbiss, Waterhouse (2011): Phasic and Tonic Patterns of Locus Coeruleus Output Differentially Modulate Sensory Network Function in the Awake Rat; Neurophysiol. 2011 Jan; 105(1): 69–87.; doi: 10.1152/jn.00445.2010; PMCID: PMC3023368

  32. Störungen der Hypothalamus-Hypophysen-Nebennierenrinden-Achse (HHNA), Biopsychologie Vertiefung SS 2007

  33. Haas, Konnerth (1983): Histamine and noradrenaline decreasecalcium-activated potassium conductance in hippocampal hpyramidic cells, Nature. 1983 Mar 31-Apr 6;302(5907):432-4., zitiert nach Aldenhoff, Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen (1990) in Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 182

  34. Arnsten (2009): Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009 Jun;10(6):410-22. doi: 10.1038/nrn2648.

  35. Birnbaum, Yuan, Wang, Vijayraghavan, Bloom, Davis, Gobeske, Sweatt, Manji, Arnsten (2004): Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science. 2004 Oct 29;306(5697):882-4.

  36. Bari, Robbins (2013): Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task: possible relevance to ADHD. Psychopharmacology (Berl). 2013 Nov;230(1):89-111. doi: 10.1007/s00213-013-3141-6.

  37. Aghajanian, Rogawski (1983): The psychological role of alpha-adrenoceptors in the CNS: new concepts from cingle-cell studies, Trends in Pharmacological Sciences Volume 4, 1983, Pages 315-317, https://doi.org/10.1016/0165-6147(83)90417-0 zitiert nach Aldenhoff, Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen (1990) in Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 182

  38. Aston-Jones, Rajkowski, Cohen (2000): Locus coeruleus and regulation of behavioral flexibility and attention. Prog Brain Res. 2000;126:165-82.

  39. Ranjbar-Slamloo, Fazlali (2020): Dopamine and Noradrenaline in the Brain; Overlapping or Dissociate Functions? Front Mol Neurosci. 2020 Jan 21;12:334. doi: 10.3389/fnmol.2019.00334. PMID: 32038164; PMCID: PMC6986277.

  40. El Mansari, Guiard, Chernoloz, Ghanbari, Katz, Blier (2010): Relevance of norepinephrine-dopamine interactions in the treatment of major depressive disorder. CNS Neurosci Ther. 2010 Jun;16(3):e1-17. doi: 10.1111/j.1755-5949.2010.00146.x. PMID: 20406250; PMCID: PMC2904493. REVIEW

  41. Guiard, El Mansari, Blier (2008): Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus ceruleus, and dorsal hippocampus. Mol Pharmacol. 2008 Nov;74(5):1463-75. doi: 10.1124/mol.108.048033. PMID: 18703671.

  42. Carrettiero, Almeida, Fior-Chadi (2008): Adenosine modulates alpha2-adrenergic receptors within specific subnuclei of the nucleus tractus solitarius in normotensive and spontaneously hypertensive rats. Hypertens Res. 2008 Dec;31(12):2177-86. doi: 10.1291/hypres.31.2177. PMID: 19139607.

  43. Sugama, Takenouchi, Hashimoto, Ohata, Takenaka, Kakinuma (2019): Stress-induced microglial activation occurs through β-adrenergic receptor: noradrenaline as a key neurotransmitter in microglial activation. J Neuroinflammation. 2019 Dec 17;16(1):266. doi: 10.1186/s12974-019-1632-z. PMID: 31847911; PMCID: PMC6916186.

  44. Stahl (2008): Depression and bipolar disorder: Stahl’s essential psychopharmacology, Seite 22 ff

  45. Sánchez-Soto, Bonifazi, Cai, Ellenberger, Newman, Ferré, Yano (2016): Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist. Mol Pharmacol. 2016 Apr;89(4):457-66. doi: 10.1124/mol.115.101808.

  46. Duan, Wang (2010): Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. PMID: 20858707; PMCID: PMC2993547.

  47. Böhm (2020): Dopaminerge Systeme, in: Freissmuth, Offermanns, Böhm (Herausgeber): Pharmakologie und Toxikologie. Von den molekularen Grundlagen zur Pharmakotherapie.

  48. Koepsell (2021): General Overview of Organic Cation Transporters in Brain. Handb Exp Pharmacol. 2021;266:1-39. doi: 10.1007/164_2021_449. PMID: 33782773.

  49. Jones, Gainetdinov, Jaber, Giros, Wightman, Caron (1998): Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34. doi: 10.1073/pnas.95.7.4029. PMID: 9520487; PMCID: PMC19957.

  50. Solanto (1995): Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration; Behav Brain Res. 1998 Jul;94(1):127-52