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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)¶
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:
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, particularly 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 PFC17
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 system18
By norepinephrine from there influencing neurons in the medulla oblongata, which in turn excite preganglionic neurons.18
Amygdala and PFC (relevant for emotional experience).19Permanent stress leads to permanently elevated norepinephrine levels and subsequently to a downregulation of the corresponding adrenoceptors (norepinephrine receptors) in
Periaqueductal gray (relevant for behavior control)19
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
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 viewed neurologically
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
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 is distinct from the dopaminergic 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 more frequently than average in carriers of the DRD4 7R polymorphism26 Whether it is a pathological brain maturation delay or the prolonged brain maturation typical of more gifted individuals (⇒ Giftedness and ADHD) is an open question. High sensitivity is associated with the DRD4 7R polymorphism as a risk/opportunity gene. See more at ⇒ How ADHD develops: genes + environment.
The norepinephrine transporter, which also picks up dopamine, appears to be reduced in ADHD in right hemisphere attention networks.27
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¶
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
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.
One study replicated other studies that children with ASD have increased tonic (resting pupil diameter) and decreased phasic (PDR and ERP) activity of the locus coreuleus-norepinephrine system. Tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptomatology33
Norepinephrine receptors are also called adrenoceptors. The three norepinephrine receptor types are distinguished on the basis of norepinephrine affinity:3
D4R thereby modulate 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 ADHD development mediated by D4.7R. As with the pineal β1R-D4R and α1B-D4R heteromers, the
Cortical α2AR-D4.4R heteromers might act as noradrenaline sensors that are activated at high noradrenaline levels and that 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 norepinephrine (via D4.7R) for α2AR facilitates the α2AR-mediated inhibitory effect on P neurons
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
Phasic stimulation in alarm situations40
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 may explain the common experience why some noradrenergic drugs work very well initially but quickly lose this effect.
Inhibits beta 2 - receptors
Dopamine
Dopamine can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus414243
In PFC and nucleus coeruleus
In the cortex, preferentially localized postsynaptically in P neurons of the deep layers4445
Α2AR-D4R heteromers in significant quantity in mouse cortex46
Activation of cortical postsynaptic α2AR showed two opposing neuronal effects:35
Both dependent on Gi protein-mediated decrease in cAMP formation
Presumably, two distinct functional populations of α2AR exist:
Arousing effect
Dependent on the inactivation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN)47
Presumably mediates the therapeutic effects of α2AR agonists by counteracting ADHD cortical frontal hypoactivity44
Inhibitory effect
Dependent on the inactivation of AMPA receptors4849
Might be mediated by own population of α2AR, which is a protective mechanism in case of overstimulation by high norepinephrine release under stress conditions48
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.51
Norepinephrine action at the β-receptor: excitatory, reducing potassium currents.34
Β-Antagonists
Cause improved sustained attention and performance in stop-signal tasks (SST).38
These are always alpha 2 receptors.52 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 ≥ D2LR.53 Dopamine, in turn, can directly activate α2-adrenoceptors in the locus coeruleus and hippocampus.414243
Noradrenaline transporters (like DAT) are always located at the presynapse.
The norepinephrine transporter also takes up dopamine. The norepinephrine transporter appears to be reduced in ADHD in the attention networks of the right cerebral hemisphere.27
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.54
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.54 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.55
OCT3 appears to occur mainly peripherally and rarely in the brain.54
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.
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.57 This should also be true for norepinephrine.
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 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.58
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
Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 215 ↥
