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Neurotransmitters in stress

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Neurotransmitters in stress

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Neurotransmitters are important factors in the generation and mediation of stress within the body.

1. Neurotransmitters that activate the stress systems

The major neurotransmitters that activate CNS stress systems include1

  • from the locus coeruleus (A1/A2) and in the autonomic nervous system
    • Norepinephrine
  • from the hypothalamus
    • AVP
    • CRH
  • pro-opiomelanocortin derived peptides
    • a-Melanocyte Stimulating Hormone
    • ß-endorphin
  • from the raphe nuclei in the midbrain
    • Serotonin
  • from the posterior hypothalamic histaminergic system
    • Histamine

2. Dysfunction of the dopamine system during stress

Stress directly activates the dopaminergic system in the brain (CNS),2 which is centrally impaired in ADHD.

A meta-analysis of a large number of studies found that during acute stress, dopamine levels and dopamine metabolism increased particularly in the PFC, but less so in other subcortical areas.34

Acute stress increases DA levels in healthy rats

  • In the mPFC by 95
  • In the nucleus accumbens by 39
  • In the striatum by 255

Dopamine is essentially projected from the ventral tegmentum to the PFC and nucleus accumbens during stress responses, with projection to the PFC being particularly sensitive to stress.674

  • Dopamine plays a role in the hedonic and reward aspects of stress.
  • The effects of stress on sexual activity and appetite, as well as on affinity for substance abuse, are thought to be mediated by the dopamine system.
  • Dopamine increases the ability of neuronal information processing and thus learning and information processing in relation to the stressor that has occurred.
  • The amygdala (central nucleus there) influences dopamine neurotransmission in the PFC. Lesions of the central amygdala block stress-induced dopamine release in the PFC. Infusion of AMPA into the central nucleus of the amygdala causes a rapid increase in dopamine in the PFC as well as (thereby) increased arousal.84 This is consistent with the role of the amygdala in coordinating neural systems to regulate behavior during stress

2.1. Different types of stress cause different dopamine effects

Not all stress is the same. Depending on the type of stress, different effects on the dopamine system are triggered.

The types of stress differ according to:

  • Duration and intensity of stress
    Mild stress slightly increases dopamine levels (as well as norepinephrine levels) in the PFC, improving cognitive performance. Severe stress extremely increases dopamine levels and norepinephrine levels in the PFC and causes the PFC to shut down. Behavioral control is outsourced to other parts of the brain.
  • Type of stressor Each stressor has its own specific effects on neurotransmitters. Different stressors include.
    • Psychological stress
    • Physical pain
    • Injuries
    • Cold
    • Heat
    • Diseases

All stress symptoms each have their own neurophysiological correlates.
A neurophysiological correlate means that along with the symptom, a specific activity or change occurs in a specific area of the brain.

2.1.1. Light/heavy - short/long - early/late stress

  • Low stress levels are primarily processed in the mesoprefrontal system. Other ascending dopaminergic systems are not affected.94 This could be due to a significantly lower number of inhibitory D2 autoreceptors in the mesoprefrontal area and extensive excitatory signals to the ventral tegmentum.
  • Mild stress increases dopamine, serotonin, and norepinephrine metabolism10 in mPFC11
    • Serotonin influences
      • The hypothalamus (part of the HPA axis / stress regulation axis)
      • The amygdala, which activates the HPA axis
      • The hippocampus, which inhibits the HPA axis.
  • Mild stress (not too prolonged) causes slightly elevated levels of norepinephrine and dopamine in the PFC.
  • Slightly elevated levels of norepinephrine and dopamine increase the activity of the PFC and thus its cognitive and executive performance.
  • Highly elevated levels of dopamine and/or norepinephrine shut down the PFC and shift behavioral control to other brain areas.
  • Short-term intense stress massively increases dopamine levels in the PFC.
  • Chronic early childhood stress decreases dopamine levels in the nucleus accumbens through downregulation.12
  • Dopamine in the mPFC normally suppresses mesolimbic dopamine transmission. However, this no longer succeeds during extreme or unpredictable stress. Dopamine innervation also appears to be important for stress-induced activation of neurons in the stria terminalis (anterolateral BNST).134 involved in both the activation of higher-order stress-dependent circuits and the generation of coping behaviors.
  • Increased dopamine levels in the mPFC lead to a decrease in dopamine levels in the nucleus accumbens in the striatum (reinforcement center), which in the long term could lead to overactivation of dopamine transporters there via upregulation, which is a major problem in ADHD.
  • Chronic stress leads to a decrease in dopamine levels in the PFC via downregulation (increase in the number of dopamine transporters and dopamine receptors).
  • Nevertheless, in chronic stress, the reduced level of dopamine in the PFC after downregulation is associated with
    • With overexcitation of the PFC
    • With a reduction of the dopamine level in the nucleus accumbens in the striatum
  • Chronic early childhood stress (daily hand-holding in rats, handling) leads to increased dopamine metabolism in the nucleus accumbens in adulthood. This results from a loss of inhibitory control by the right mPFC due to a dopamine deficiency found there. The dopamine deficiency in turn correlates with an increase in the number of dopamine transporters.14
  • The long-term nature (chronification) of stress and the degree of control over the stressor alters dopamine-dependent behaviors and activation of afferents to the nucleus accumbens.154

2.1.2. Different stressors

Each stressor has its own specific effect on dopamine.16

2.1.2.1. Psychological stress
  • Psychological stress appears to activate dopaminergically only the D2 receptor system.17
  • Psychosocial stress
    • Increases the number of D2 receptor binding sites in the hippocampus.18
    • Reduces the binding of the ligand 3 H-WIN 35,428 for the dopamine transporter in the striatum after a period of 4 weeks.17
    • Chronic psychosocial stress causes “shrinkage” of dendrites of pyramidal neurons in the CA 3 region of the hippocampus.19
    • Chronic social stress reduced in mice20
      • In the hypothalamus: dopamine, noradrenaline and serotonin levels
      • In the PFC: serotonin and dopamine levels
    • Alcohol in the striatum did not increase dopamine levels in defeated mice, whereas dopamine levels increased in nondefeated mice
  • Taking in hand (of mice; handling)
    • Increases dopamine level
      • In mPFC2122
      • In the nucleus accumbens (however small)22
    • Does not change dopamine levels
      • In the striatum22
  • Acute physical constriction (fixation)
    • Increases dopamine in the mPFC and nucleus accumbens (mesolimbic dopamine system)23 and acetylcholine in the hippocampus.24
    • The dopamine increase in the mPFC and nucleus accumbens, like the acetylcholine increase in the hippocampus, occur as well on subsequent release, so this could be a correlate of emotional arousal due to sudden environmental change.2423
    • Increases the concentrations of the dopamine metabolite DOPAC in PFC and nucleus accumbens25
    • Induces Fos immunoreactivity in dopamine neurons of the ventral tegmentum (VTA), but not in the substantia nigra26
  • Stress due to new environment
    • Increases dopamine levels in the right PFC27
  • Anxious behavior in the open environment
    • Correlates with increased dopamine levels in the right PFC28
  • Escape behavior to shocks
    • Correlates with increased dopamine levels in the right PFC29
2.1.2.2. Injuries and infections
  • Injuries and infections activate the D1 and the D2 receptor system17
2.1.2.3. Repeated infliction of pain
  • Electrical shocks
    • Activate the mesolimbic dopamine system2423
    • Increase FOS expression
      • In prelimbic and infralimbic cortexes30
      • In tyrosine hydroxylase-labeled neurons of the ventral tegmentum (VTA)30
  • Tail bruising in mice
    • Increase dopamine level

      • In mPFC22

      • In the nucleus accumbens (however small)22

      • Do not change dopamine levels

        • In the striatum22
2.1.2.4. Birth stress
  • Oxygen deficiency during birth leads to increased dopamine metabolism in the nucleus accumbens in adulthood. This results from a loss of inhibitory control by the right medial prefrontal cortex (PFC) due to a dopamine deficiency found there. The dopamine deficiency in turn correlates with an increase in the number of dopamine transporters.14
2.1.2.5. Hypotension
  • Increases the level of dopamine in the mPFC314
2.1.2.6. Conditioned stress
  • Increases the dopamine level and serotonin level in the
  • Does not change dopamine levels in
    • Perirhinal cortex324
    • Cingulate cortex324
    • Basolateral amygdala324
    • Striatum324
  • Acute conditioned stress should only increase norepinephrine levels in the mPFC, but not dopamine levels.33

2.2. Dopaminergic neurophysiological correlates of various stress responses

Different stress responses have different dopaminergic neurological correlates.

  • Frightfulness
    • Is controlled by increased dopamine in the dorsal striatum and by stimulation of the substantia nigra pars compacta (which produces dopamine).2
    • Dopamine release in the mesolimbic system (nucleus accumbens = ventral striatum) by electrical stimulation of the ventral tegmentum promotes **aversively motivated learning
  • Learning from stress experiences
    • Drug-induced blockade of dopamine receptors in the amygdala prevents this.2
  • Maintaining attention to problem solving
    • Is controlled by the dorsolateral PFC.34
  • Selective attention (attention directing)
    • Is controlled by the dorsal anterior cingulate cortex.34
  • Hyperactivity
    • Is provided by the OFC35 and
    • Controlled by the prefrontal motor cortex.34
  • Impulsivity
    • Is supported by the OFC and the
    • Cortico-striatal-thalamocortical loop (cortex-striatum-thalamus regulatory circuit) controlled.36
  • Conditioned stress
    • Lesions of the left and right amygdala suppress a dopamine increase in the mPFC and other stress responses to conditioned stress.11
  • Conduct Disorder (CD)
    • Controlled by a network of the ventromedial PFC and the limbic system37
  • Oppositional defiant behavior (ODD)
    • Controlled by a network of the ventromedial PFC and the limbic system37
  • Aggression
    • Controlled by a network of the ventromedial PFC and the limbic system37
  • Anxiety disorders
    • Controlled by a network of the ventromedial PFC and the limbic system37
  • Bipolar disorder
    • Controlled by a network of the ventromedial PFC and the limbic system37

3. Norepinephrine, adrenaline and stress

In the CNS, stress is primarily modulated by norepinephrine38

  • Moderate norepinephrine levels
    • Strengthen the function of the PFC
  • High norepinephrine levels
    • Switch off the PFC (which impairs analytical thinking)
    • Strengthen the sensorimotor and affective regions of the brain (which intensifies perception and emotion)

Activation of microglia by stress appears to be mediated by norepinephrine via β1- and β2-adrenoceptors but not via β1-AR β3-adrenoceptors or α-adrenoceptors.39

Second graders showed elevated levels of cortisol on exam days and concomitant decreased levels of epinephrine and norepinephrine. Individual differences in secreted hormones were significantly related to personality variables observed in the classroom and to the effects of academic stress:40

  • Social approach behavior correlated with higher cortisol and adrenaline levels
  • Fidgetiness correlated with low adrenaline levels
  • Aggressiveness correlated with high levels of norepinephrine
  • Inattention correlated with low levels of norepinephrine

4. Serotonin and stress

The ascending serotonergic pathways, originating in the midbrain (nuclei raphe), accompany the locus ceruleus-derived central stress response by releasing serotonin.1

There is a relationship between serotonin and sensitivity to stress. However, the results are heterogeneous and the causes and the correlations are still unclear.41
There is a relationship between serotonin and cortisol levels.
Stress increases serotonin levels in healthy individuals42 as well as norepinephrine, dopamine and cortisol levels43.
Acute stress, on the other hand, is thought to decrease serotonin production by dorsal raphe nuclei, whereas fluoxetine stimulates serotonin production.44
Severe, life-threatening stress appears to increase serotonin 2-A receptor function and expression, as found in PTSD. Paradoxically, the PTSD drug 3,4-methylenedioxymethamphetamine acts as a serotonin 2-A receptor agonist.45

If the adrenal cortex is removed so that cortisol can no longer be secreted,

  • This alters the release of serotonin in the dorsal raphe nuclei (DRN)
    • Not for nomal conditions
    • However, it reduced under stress
      Stimulation of glucocorticoid receptors in the DRN then disrupts stress-induced serotonin blockade.41
  • Avoids chronic unpredictable stress46
    • The depression that normally develops
    • But not the fear that normally arises
      • In the development of which the mineralocorticoid receptor is involved
      • Which is closely associated with cell proliferation in the hippocampus
  • This increases serotonin levels and TPH2 expression in the hippocampus in response to chronic unpredictable stress.46

Repetitive stress increases serotonin production more than single stress47 and leads to apical dendrite reduction in the medial PFC, which decreases the number of excitatory postsynaptic events mediated by serotonin and orexin/hypocretin. Cortisol did not produce this consequence. A GR antagonist given before stress avoided the reduction in excitatory postsynaptic events mediated by serotonin but not those mediated by orexin/hypocretin.48

Chronic stress increases cortisol levels through release of vasopressin rather than CRH.47

Cortisol increases serotonin levels in the amygdala and PFC49 and in the hippocampus.47 This probably occurs through activation of glucocorticoid receptors. This is because inhibition of monoamine oxidase increases serotonin levels, whereas a decrease in cortisol levels prevents this increase in serotonin (caused by monooxidase inhibition).50 This effect of cortisol lasts a long time (as with SSRIs) and probably occurs by desensitizing the serotonin 1-A autoreceptor.51 However, the desensitization of the serotonin 1-A autoreceptor caused by SSRIs such as fluoxetine appears to act independently of the glucocorticoid receptor.52

Removal of the adrenal gland (in whose “cortex” cortisol is produced) causes41

  • Unchanged serotonin transporter expression in the dorsal raphe nuclei (where serotonin is produced)
  • Unchanged [3H]cyano-imipramine binding to serotonin transporters in dorsal raphe nuclei
  • Unchanged [3H]citalopram binding to mesencephalon (midbrain) serotonin transporters
  • Decreased serotonin reuptake in the mesencephalon (midbrain)
  • With concomitant long-term administration of MR- and GR-binding corticosteroids, no change in serotonin transports in dorsal raphe nuclei, medial raphe nuclei, or mesencephalon

In healthy rats, caused41

  • Acute corticosterone administration unchanged serotonin reuptake in the mesencephalon (midbrain)
  • A long-term infusion of dexamethasone (a stronger GR agonist than MR agonist)
    • Decreases serotonin transporter expression in the midbrain
    • But does not affect them in the hippocampus or PFC.
  • Short-term stress has no effect on serotonin transporter density in the midbrain
  • Prolonged stress (21 days)
    • Increases [3H]cyano-imipramine binding in the dorsal raphe nuclei
    • Increases (to a lesser extent) serotonin transporters in medial raphe nuclei

Serotonin interacts extensively with BDNF in terms of53

  • Aggression
  • Depression
  • Drug addiction
  • Suicidality
  • Stress regulation
  • Brain plasticity

4.1. Serotonin deficiency and stress

Serotonin deficiency via deprivation of the serotonin precursor tryptophan activated the HPA axis as did another stressor, but did not produce synergistic stress axis effects with it.5455

SSRI administration reduced PTSD symptom severity in children and adults in one study.56

Serotonin deficiency is clinically evident in association with53

  • Depression
  • Fear
  • Impulsivity
  • Suicidal tendencies
  • Schizophrenia.

4.2. Serotonin transporters and stress

Decreased serotonin transporter binding affinity correlates with increased cortisol stress response and increased anxiety.57

Regarding the serotonin transporter genotype, various studies found that

  • No significant effect on cortisol stress response or mood57
  • That the 5-HTTLPR short/short genotype correlates with a higher cortisol stress response
    • In young adults to psychosocial stress58
    • In newborns to a physical stressor59
  • That the group of 5-HTTLPR short genotypes (SS, SLG, LGLG, SLA, LGLA) correlated with a greater frequency of early childhood stress experiences in the first 5 years of life compared with 5-HTTLPR long/long (LALA) in younger adults but not in children.60
  • Twins who had suffered bullying had higher serotonin transporter methylation at the age of 10 years than their twin siblings without bullying experience. Twins with later (!) bullying experience showed increasing methylation compared to their non-bullied twin siblings already at 5 years of age, before this (!) bullying experience. Children with higher serotonin transporter methylation levels showed a flattened cortisol stress response.61 This may be related to the fact that people with impairments (such as ADHD) are more likely to be victims of violence. ADHD increased the likelihood 2.7-fold, according to one study.62
  • That the group of 5-HTTLPR short genotypes (SS, SLG, LGLG, SLA, LGLA) in combination with many early childhood stress experiences in the first 5 years of life
    • Correlates with a high cortisol stress response to the TSST.60 Similar results were found in several other studies.636465
  • That 5-HTTLPR long/long (LALA) in combination with few early childhood stress experiences in the first 5 years of life
    • Correlated with a high cortisol stress response to the TSST63
    • Which another study found only in younger adults60
    • While another study found no correlation65

5. Histamine and stress

The posterior hypothalamic histaminergic system accompanies the locus ceruleus-derived central stress response by releasing histamine.1

6. The stress hormones CRH, cortisol and stress

CRH and cortisol are not neurotransmitters, but hormones produced by the hypothalamus as the first stage of the HPA axis (CRH) and the adrenal cortex as the last stage of the HPA axis (cortisol), respectively.
Because the HPA axis is essential for understanding stress and ADHD, we refer here to the detailed account at ⇒ The HPA axis/stress regulation axis and ⇒ Cortisol in ADHD.

Older adults

  • With a low number of stressful life experiences in the first 15 years of life showed the highest cortisol stress response60
  • With a high number of stressful life experiences in the first 15 years of life showed the lowest cortisol stress response60

While some authors60 consider a low cortisol stress response to be a measure of a healthy response, we question whether an average cortisol stress response is not healthy, and whether a particularly low cortisol stress response, as well as an excessive cortisol stress response, is a sign of a stress system imbalance, as is the case with the cortisol stress response.

7. Stress/ADHD symptoms due to too high or too low catecholamine levels

7.1. Optimal neurotransmitter level = optimal information transmission

Optimal information transmission between brain synapses requires an optimal level of the respective neurotransmitters. A neurotransmitter level that is too low leads to an almost identical signal transmission disturbance as a neurotransmitter level that is too high (reversed-U theory).66676869687071727374757677

For optimal signal transmission, the pyramidal cells of the PFC require moderate stimulation of D1 receptors by dopamine and α2A receptors by norepinephrine. Dopamine binding to D1 receptors reduces the noise of the input signal in the PFC by reducing signals from external sources that are not needed, whereas norepinephrine amplifies the incoming signal from external sources via α2A receptors.78

Increased DA and NE levels cause additional occupancy of receptors, which reduces attention. Decreased DA and NE levels cause all incoming signals to be identical, which reduces concentration on individual tasks.

Thus, too high as well as too low DA and/or NE levels lead to very similar symptoms due to non-optimal signal transmission in the PFC.79

Therefore, a medication that increases neurotransmitter levels and that works well at low doses may, at higher doses, cause the very symptoms that it avoids at low doses. This is why it is malpractice to start medications for ADHD at the target dosage or to dose them quickly. It is better to start the titration phase (medication phase) very slowly and low than too fast and too high.

Example:

Adult nonsmokers were treated with nicotine patches in a small study.
For those with poor concentration ability, it improved; for those with good concentration ability, it worsened.80
Nicotine has a similar effect to stimulants, only cholinergic instead of dopaminergic; it therefore increases the level of the neurotransmitter acetylcholine. Too low an acetylcholine level causes concentration difficulties.
Nicotine patches may be effective medications for ADHD.
⇒ Nicotine in ADHD

7.2. Stress/ADHD symptoms due to elevated catecholamine levels (DA / NE)

7.2.1. Acute stress increases dopamine levels in the mPFC, striatum, and nucleus accumbens

Stress increases dopamine levels in healthy rats

  • In the mPFC by 95
  • In the nucleus accumbens by 39
  • In the striatum by 258182

Stress involves a phasic (i.e., short-term) increase in dopamine.83

7.2.2. Mild acute stress = mild NE/DA elevation = increased cognitive performance

The mild stress responses of the autonomic nervous system are mediated by acetylcholine and adrenaline.

In the central nervous system (brain), slight increases in dopamine and/or norepinephrine levels cause increased PFC performance (except in carriers of the COMT Met158Met gene polymorphism).8485868788

If this does not solve the problem (the stressor is not eliminated), dopamine and norepinephrine levels continue to rise. High levels of norepinephrine activate the HPA axis (stress axis), which thus only comes into action when stress is difficult to manage.

7.2.3. Severe acute stress = severe NE/DA and cortisol elevation = decreased cognitive performance

7.2.3.1. High norepinephrine blocks PFCs

In contrast to mild norepinephrine increases that stimulate the PFC, large increases in norepinephrine shut down the PFC and shift behavioral control to posterior brain regions.38899091929394

This is likely to correspond to the effect described as posteriorization by Dietrich95 with reference to Mobbs et al96.

7.2.3.2. High cortisol levels block PFCs

High cortisol levels, as they occur especially in ADHD-I and SCT during acute stress, additionally stimulate norepinephrine-α1 receptors in the PFC, through which norepinephrine already impairs PFC and working memory function. Simultaneous addressing of these receptors by norepinephrine and cortisol enhances this effect.97
In addition, the shift of control from cognitive brain regions (PFC and hippocampus) to more behavioral brain regions (such as aymgdala and dorsal striatum) is regulated by the cortisolergic mineralocorticoid receptors (MR) and glucocorticoid receptors (GR).98

Cortisol, which is often elevated as a stress response in ADHD-I and presumably SCT, blocks retrieval of declarative (explicit) memory via glucocorticoid receptors (GR) in the PFC and hippocampus. Nondeclarative (implicit, intuitive) memory is not affected.99 This could explain the thinking and memory blocks often associated with ADHD-I and also why ADHD-I sufferers are often reported to have higher intuition. That the shift in the focus of memory skills leads to a shift in problem-solving patterns would be obvious in any case. Trappmann-Korr calls this “holistic” perception. However, our own data collection to date shows that a self-assessment of being intuitive is present in 69% of ADHD-HI sufferers and only in 60% of ADHD-I sufferers. (n = 1,100, as of August 2019)
It is likely that not only retrieval (remembering) but also acquisition (learning) and memory consolidation (long-term storage) of information are impaired. Consolidation occurs especially during sleep in the first half of the night, which is characterized by particularly low basal cortisol levels. Consolidation can be prevented by low cortisol administration.99

Cortisol stress response does not correlate with thinking blocks

Our hypothesis that thinking blocks would occur less frequently in ADHD-HI than in ADHD-I was not confirmed by the analysis of about 1700 records of the ADxS online symptom test. Thinking blocks occurred about equally frequently in ADHD-HI as in ADHD-I, according to our data.

Evidence suggests that high levels of norepinephrine shut down the PFC via α1-receptors.

We had assumed that ADHD-HI sufferers (due to a simultaneously reduced noradrenaline stress response in parallel to the reduced cortisol stress response) would have to suffer blockades of the PFC and the associated thinking and decision-making problems less frequently, whereas ADHD-I sufferers (without hyperactivity/impulsivity) would suffer a frequent short-term exaggerated stress response and more frequent shutdown of the PFC (by norepinephrine and cortisol) because of an increased phasic cortisol stress response and a concomitant increased phasic norepinephrine release to acute stress, which could trigger more frequent thinking blocks. ⇒ Neurotransmitters in stress

Because the intensity of norepinephrine release stimulates the intensity of cortisol release, we had hypothesized that cortisol and norepinephrine stress responses would run in parallel. Because quite a few data suggest that ADHD-I correlates with increased cortisol stress responses, if cortisol and norepinephrine stress responses were correlated, it would have been logical that the increased cortisol stress responses typical in ADHD-I would be associated with increased stress-induced release of norepinephrine and consequent increased α1-adrenergic receptor activation.

However, the equal frequency of thinking blocks in ADHD-HI as ADHD-I sufferers suggests that this hypothesis is not correct.

7.2.3.3. Details

Since the PFC controls the HPA axis, the removal of control by the PFC further disinhibits it.
Other voices distinguish between short-term stress, which increases the PFC’s cognitive performance, and long-term stress, which decreases it,100 which should coincide in result.

Slightly elevated catecholamine levels postsynaptically activate alpha2A adrenoceptors (through norepinephrine) and D1 receptors (through dopamine), thus enhancing prefrontal regulation of behavior and attention, whereas severely elevated catecholamine levels worsen prefrontal functions by stimulating noradrenergic alpha1 adrenoceptors and (excessively) dopaminergic D1 receptors.10173
Alpha1-adrenoceptors are less sensitive than alpha2A-adrenoceptors and therefore respond only to higher levels of norepinephrine. When norepinephrine levels are high enough to activate not only alpha2a but also alpha1 adrenoceptors, alpha1 adrenoceptors inhibit the cognitive performance of the PFC.10291103104
See also the illustration of the adrenoceptors = norepinephrine receptors at ⇒ Norepinephrine.

Physiological stressors such as traumatic brain injury105 or hypoxia106 appear to induce similar physiological effects in the PFC as psychological stress. Physical stressors also induce the release of catecholamines in the mPFC and activate the same intracellular signaling events (e.g., activation of the cAMP-PKA pathway) associated with the loss of dendritic spines and impairment of working memory. Apparently, various stressors (physical as well as psychological) can affect the structure and function of the PFC.101

Alpha1-adrenoceptor antagonists (blockers) are used to treat PTSD.

Elevations in cortisol are associated with stress-induced release of norepinephrine and α1-adrenergic receptor activation.107108
The increase in cortisol levels after stress is mediated by activation of the adrenergic system and α1-adrenergic receptors, in that a large increase in norepinephrine activates alpha1-adrenoceptors in the hypothalamus, leading to the release of the stress hormone CRH, which activates further stages of the HPA axis (release of ACTH and cortisol).107109108110
CRH dose-dependently reduces the performance of the PFC (especially working memory). CRH antagonists abolish this effect.111112

Activation of alpha1-adrenoceptors by high levels of norepinephrine thus causes high levels of cortisol as well as attention problems.113

Norepinephrine levels in the OFC and amygdala correlate with activation of the HPA axis in healthy individuals. In contrast, this correlation is inverted in severely overweight people.110

7.2.4. PFC and amygdala - stress phenotypes

The activity of the PFC is inverse to the activity of the amygdala. An active PFC correlates with a less active amygdala and vice versa.114
It is known that anxiety and depression occur more frequently in people who internalize stress, i.e. who tend to eat stress up inside themselves (internalizing, ADHD-I subtype) rather than acting it out externally (externalizing, ADHD-HI/ADHD-C). In the latter, externalizing disorders such as aggression disorders (oppositional defiant disorder; social behavior disorder, borderline) predominate.

With this in mind, the fact that ADHD-I has a higher incidence of the disorder patterns associated with an activated amygdala, such as anxiety and depression, suggests that the PFC is more frequently deactivated in ADHD-I than in ADHD-HI. Together with the fact that increases in cortisol are associated with stress-induced release of norepinephrine and α1-adrenergic receptor activation,107108 this leads us to hypothesize that in ADHD-I, norepinephrine release in response to acute stress should be very frequently excessive, analogous to cortisol release, causing a more frequent shutdown of the PFC and shift of behavioral control to subcortical brain regions, whereas in ADHD-HI, which is frequently associated with decreased cortisol release on acute stress, there should be a correlating decreased norepinephrine release, leading less frequently (and, from the perspective of inability to recover, perhaps even too infrequently) to downregulation of the PFC.

7.2.5. Dopamine in stress and ADHD

DAT knockout mice, which have almost no dopamine transporters (DAT) (thus representing a kind of neurological anti-model to ADHD in which too many DAT are present) have some symptoms like ADHD sufferers:115

  • Hyperactive
  • Learning problems
  • Memory problems

The disorders frequently occurring comorbidly with ADHD

  • Conduct disorder (CD)
  • Oppositional defiant behavior (ODD)
  • Psychosis
  • Bipolar

are typically associated with extremely elevated levels of dopamine in some areas of the brain.79

7.3. Stress/ADHD symptoms due to too low catecholamine levels (DA / NE)

Massive dopamine deficiency in the striatum leads to a massive disturbance of drive. The interest In pleasure is reduced, while the pleasureability per se is not impaired.

However, dopamine deficiency is only one way to cause the symptoms mentioned. Dopamine excess causes largely identical symptoms, since what matters most is a deviation from a dopamine level optimal for signal transmission (see above under 1.1. and 1.2.).

  • Rats that had their ascending dopaminergic pathways almost completely destroyed, leaving 99% less dopamine available, subsequently lacked the drive to ingest the sugar solution they had previously preferred. This phenomenon was thus caused by dopamine deficiency in the brain’s reinforcement center (striatum). At the same time, the animals’ ability to perceive pleasure was still unchanged when the sugar solution was fed to them, as could be seen from typical tongue movements made by rats when they were presented with foods they found pleasurable. Moreover, this pleasure response could be enhanced by hedonic activating substances (e.g., benzodiazepines) and attenuated by concurrent unpleasant stimuli.116117
  • The neurotoxin 6-hydroxydopamine selectively destroys dopaminergic neurons. Animals treated in this way develop hyperactive behavior118
    • According to other accounts, 6-hydroxydopamine, on the other hand, has a more noradrenergic effect.119 Norepinephrine is also significantly involved in ADHD.
    • Dopamine level disturbances by 6-hydroxydopamine showed a major role of D4 receptors in the caudate nucleus (but not of D2 receptors) in the development of hyperactivity.120
  • Those affected by the 1914 to 1917 encephalitis epidemic developed typical ADHD symptoms. Children developed hyperactive motor skills, and adults developed Parkinson’s symptoms. Encephalitis destroys the cells in the substantia nigra that produce dopamine. This cause could be reproduced in animal experiments as the trigger of the symptoms. Thus, the symptoms are consequences of dopamine deficiency.121 In an ADHD diagnosis, encephalitis must also be clarified as a differential diagnosis today.
  • Perinatal hypoxia leading to early infantile brain damage (FKHS) causes demise of dopaminergic cells in the striatum, resulting in a decrease of dopamine levels in the striatum by up to 70%.
  • In people with Parkinson’s disease, the cells of the substantia nigra are damaged, reducing the synthesis of dopamine by up to 90 percent. This causes motor impairments such as rigor, tremor and akinesia. Depression is many times more common in Parkinson’s sufferers, which is also likely to be due to the dopamine deficiency.122
  • Cocaine or amphetamine abuse causes downregulation of the body’s dopamine synthesis. After cocaine intake is discontinued, hyperactivity develops as a withdrawal symptom due to the now too low dopamine levels.123
  • Nicotine, consumed earlier and more frequently by ADHD sufferers,124 increases dopamine release in nigrostriatal and mesolimbic areas, thereby improving attention.125126
  • Toxins such as polychlorinated biphenyls, which inhibit dopamine synthesis as well as the storage of dopamine in the vesicles and its release, thereby causing an excessively low level of dopamine, also cause hyperactivity and impulsivity (in rats even at subtoxic doses).127
  • Dysphoria is caused by dopamine deficiency (according to Wender-Utah, dysphoria with inactivity is a core symptom of ADHD in adults).128

That dopamine deficiency is involved in mediating ADHD symptoms is demonstrated by the very good effects of medications that result in increased dopamine levels or mediate an enhanced response to dopamine. Stimulants (methylphenidate, amphetamine drugs) as well as atomoxetine act as dopamine reuptake inhibitors (which increases the availability of dopamine in the synaptic cleft) and stimulate dopamine production.

Nevertheless, not all drugs that increase dopamine levels are helpful in ADHD. The dopamine agonists L-dopa (levodopa), amantadine, and piribidel, for example, have no positive effects in ADHD despite their dopamine-increasing effects.129

  • Levodopa is a precursor of dopamine (prodrug) that can cross the blood-brain barrier and is metabolized in the brain to dopamine.130 While levodopa is helpful in Parkinson’s disease and restless legs syndrome, both of which are characterized by dopamine deficiency, it is not effective in ADHD.
  • Amantadine is a weak glutamate receptor antagonist of the NMDA receptor, increases dopamine release, and acts as a dopamine reuptake inhibitor. Its effect in Parkinson’s disease is controversial. A weak activating effect on arousal is reported in some cases.131
  • Piribedil is a piperazine derivative and therefore a non-ergot dopamine agonist.
    Piribedil is an agonist of D2 and D3 dopamine receptors and antagonist of α2-adrenoreceptor subtypes α2A and α2C. It is used against Parkinson’s disease, also together with levodopa.

While short-term stress without ADHD results in excess catecholamines (dopamine and norepinephrine) in the PFC,115 early long-term stress results in downregulation of the dopamine and norepinephrine systems. For example, chronic early childhood stress decreases dopamine levels in the nucleus accumbens.12

Exercise-restrictive stress in rats causes subsequent downregulation of dopamine in the ventral tegmentum via norepinephrine at beta-adrenoceptors in the amygdala.132

Whether there is too low or too high a level of (tonic = long-term) catecholamines in ADHD is a matter of intense debate.133
Scientific disagreement suggests that both variants occur. Possibly the subtypes and individual symptom compositions of the respective affected persons differ. It is undisputed that many ADHD sufferers have reduced dopamine levels in the PFC and striatum.
Based on current knowledge, we assume that in ADHD there is a deficiency of dopamine and norepinephrine in dlPFC, striatum, and probably cerebellum.

The typical ADHD medications (stimulants and atomoxetine act as dopamine and norepinephrine reuptake inhibitors. Stimulants increase DA and NE levels in the PFC and striatum, atomoxetine only in the PFC) increase the availability of these neurotransmitters in the synaptic cleft.

Conversely, this would have to mean that stimulants do not work for stress-induced “sham ADHD” symptoms because they raise dopamine levels, which are already above optimal, even further and thus even further away from the functional level. While dopamine and norepinephrine levels (or DA / NE action) are decreased in ADHD, people (with acute but not chronic prolonged stress) without ADHD do not have decreased but rather increased levels of dopamine and norepinephrine. Therefore, further increases in DA and NA levels should tend to exacerbate symptoms in unaffected individuals, whereas they are helpful in ADHD.

Some research suggests that these considerations may be justified:

Only low doses of methylphenidate cause an improvement in attention and executive abilities even in non-stressed healthy individuals, whereas higher doses have a negative effect.73 This corresponds to the slight DA and NE increase in mild stress, which increases cognitive abilities, and the strong DA and NE increase in severe stress, which shuts down the PFC.

However, many ADHD sufferers only respond to some ADHD medications, so that in practice no diagnostic conclusions can be drawn from a non-effect of medication alone. This is due to the large differences described above in which stress has caused downregulation in which areas of the brain in the respective affected person.

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