2. Stress by duration: long-lasting, chronic stress

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

Here we present studies on the harmfulness of long-term (chronic) stress that are not based on the age of the person with ADHD. Long-term stress causes neurological damage in people of all ages, even if this damage in older people regularly does not cause the general change in stress trigger levels typical of ADHD, but instead shows other signs of damage.

Long-term stress (prolonged stress) and stress that is too intense (trauma) can permanently damage the neuronal stress systems.¹²

Acute (short-term) stress increases the dopamine level in the PFC ³⁴
In contrast, chronic severe stress reduced the dopamine level in the PFC³ and led to a loss of dopaminergic cells in the hypothalamus, VTA and substantia nigra, as well as to a loss of noradrenergic cells in the locus coeruleus.⁵ Consequences were a reduction of dopamine levels in the striatum by around 40 % at weeks 4 and 8, while serotonin was reduced by 25 % in the striatum after 4 weeks and by 15 % after 8 weeks.
Against this background, it is hardly surprising in our view that chronic stress causes very similar symptoms to ADHD, which is also characterized by dopamine deficiency.

Chronic stress can reduce the sensitivity of receptors (downregulation). The desensitization of cortisol receptors leads to impaired stress regulation and is associated with ADHD. Other consequences of chronic stress include changes in gene expression, the neurotoxicity of stress hormones and the atrophy of certain areas of the brain. The hippocampus in particular is very susceptible to this, which impairs stress control and memory.
Chronic stress causes increased BDNF levels in the VTA/nucleus accumbens and reduced levels in the hippocampus. BDHF is important for the neuroplasticity of the brain.
The circadian rhythm is disturbed by repeated stress, which impairs sleep and the regulation of the HPA axis.

• 2.1. Damage mechanisms of chronic stress
  • 2.1.1. Downregulation / Upregulation
    • 2.1.1.1. Downregulation (receptor desensitization): Basic principle
      • 2.1.1.1.1. Downregulation during stress: desensitized cortisol receptors prevent stress system shutdown = ADHD
      • 2.1.1.1.2. Downregulation in chronic stress: glutamate receptors in the mPFC
      • 2.1.1.1.3. Downregulation in chronic stress: dopamine D2 receptors in the mesolimbic system
    • 2.1.1.2. Upregulation
  • 2.1.2. Non-specific, permanently increased excitability of nerve cells (basic principle)
    • 2.1.2.1. Noradrenaline release decoupled from external stimuli
    • 2.1.2.2. CRH receptor downregulation reduces stress system inhibition and leads to non-specific excitability
  • 2.1.3. Neurotoxic effects of stress hormones in chronic stress
    • 2.1.3.1. Glucocorticoids (cortisol)
    • 2.1.3.2. CRH
  • 2.1.4. Altered gene expression due to chronic stress
  • 2.1.5. Atrophy in various areas of the brain
  • 2.1.6. Increased neuroinflammation due to chronic stress
• 2.2. Concrete damage caused by chronic stress
  • 2.2.1. Changes in the dopaminergic system due to early or chronic stress
  • 2.2.2. Increased ΔFosB in the reward circuits
  • 2.2.3. Damage to the amygdala (increased anxiety)
    • 2.2.3.1. Enlargement of the amygdala due to serine protease “tissue-plasminogen factor”
    • 2.2.3.2. Amygdala neurons become hyperexcitable
  • 2.2.4. Damage to the hippocampus (learning and memory disorders)
    • 2.2.4.1. Early prolonged stress experiences cause a smaller hippocampus in adults
    • 2.2.4.2. Cell layer irregularities
    • 2.2.4.3. Soma shrinkage and condensation
    • 2.2.4.4. Core pyknosis
    • 2.2.4.5. Permanent stress reduces apical dendrite trees in the hippocampus
    • 2.2.4.6. Long-term stress alters cell adhesion molecules in the hippocampus
    • 2.2.4.7. Acute and chronic stress suppresses the neurogenesis of cells in the dentate gyrus of the hippocampus
    • 2.2.4.8. Cortisol increases glutamate effect on NMDA receptors in the hippocampus
    • 2.2.4.9. Noradrenaline increased
  • 2.2.5. Changes in the PFC
    • 2.2.5.1. Permanent stress reduces apical dendrite trees in the PFC
    • 2.2.5.2. Cortisol reorganizes dendrite trees in PFC and hippocampus
  • 2.2.6. Changes in the BDNF system due to chronic stress
  • 2.2.7. Changes in the serotonergic system due to chronic stress
  • 2.2.8. Changes in the cortisolergic system due to chronic stress
  • 2.2.9. Changes in the alloprenal system due to chronic stress
  • 2.2.10. Changes in the circadian system due to chronic stress
  • 2.2.11. Changes in energy storage in fat due to chronic stress
• 2.3. Mechanisms of action of acute stress
• 2.4. Different Consequences of Acute and Chronic Stress
  • 2.4.1. Consequences of acute stress
  • 2.4.2. Consequences of chronic stress

2.1. Damage mechanisms of chronic stress¶

2.1.1. Downregulation / Upregulation¶

2.1.1.1. Downregulation (receptor desensitization): Basic principle¶

Neurotransmitter systems are there to transmit signals in the brain. If the neurotransmitter level is optimal, the signal transmission also functions optimally. A neurotransmitter level that is too low disrupts signal transmission in roughly the same way as a neurotransmitter level that is too high.

Neurotransmitters are released from the sending nerve cell (presynapse) into the synaptic cleft, where they are taken up by receptors of the receiving synapse (postsynapse). The neurotransmitter is then returned to the synaptic cleft by the receiving synapse and taken up again by the sending synapse via the transporters and stored in the vesicles until the next use.
If too much of a neurotransmitter is released for a longer period of time, this leads to a desensitization of the receptors of the receiving synapse (downregulation).

The body uses downregulation and upregulation to counteract excessive (or reduced) levels of a messenger substance.

Downregulation occurs in several increments, which take place one after the other depending on the intensity and duration of the neurotransmitter oversupply:⁶

1. Desensitization
2. Receptor internalization
3. Receptor regression
4. Change in the expression of the receptor mRNA (epigenetic change in gene expression)

This happens in a similar way to nicotine, alcohol or drug abuse. Withdrawal then causes withdrawal symptoms because the desensitized receptors now receive too little of the respective (no longer artificially increased) neurotransmitters. After a few weeks of withdrawal, the relevant neurotransmitter systems recover as the receptors gradually become more sensitive again.

According to this mechanism, excessive and prolonged release of cytokines can contribute to a reduced sensitivity of immune cells to the anti-inflammatory effect of glucocorticoids.⁷ Cytokine pathways such as p38 MAPK also cause an interruption of glucocorticoid-receptor communication.⁸⁹

2.1.1.1.1. Downregulation during stress: desensitized cortisol receptors prevent stress system shutdown = ADHD¶

After its release, cortisol initially mediates the symptoms of stress by alerting many organs and areas of the brain. Afterwards, however, a high cortisol level has the effect of shutting down the stress system again, because stress is an exceptional state - a system that is designed for 100% will be damaged at some point if it is permanently at 130%.

However, as the (gluco)corticoid receptors are less sensitive after prolonged stress due to downregulation, they do not perceive this signal. The stress systems are not switched off.¹⁰ Consequences: CRH levels remain permanently elevated and permanently trigger the symptoms mediated by CRH. This mechanism has already been described for depression.¹¹⁷

The cortisol response in ADHD to an acute stressor differs by subtype. ADHD-HI and ADHD-C (with hyperactivity) often show a reduced cortisol stress response, while the ADHD-I subtype very often shows an excessive cortisol response to an acute stressor.
⇒ The HPA axis / stress regulation axis.

Understanding exactly which stress hormone system has undergone which change in which subtype could be the central key to the future treatment of ADHD.

2.1.1.1.2. Downregulation in chronic stress: glutamate receptors in the mPFC¶

Chronic unpredictable stress leads to a deregulation of the glutamate balance in mice with the Consequences of a downregulation of the glutamate receptors in the mPFC.¹² This also correlates with task switching problems.
A downregulation of glutamate receptors indicates an excessive glutamate level. This is consistent with the fact that chronic stress reduces GABA levels. GABA inhibits glutamate.

2.1.1.1.3. Downregulation in chronic stress: dopamine D2 receptors in the mesolimbic system¶

In several studies, chronic unpredictable mild stress caused anhedonia, a typical depression symptom triggered by chronic mild stress, in 70% of rats. 30% of the rats proved to be stress-resistant.¹³¹⁴
In one study, stress-resistant rats showed a downregulation of D2 receptors in the entire brain after 2 weeks, with the exception of the medial VTA (decrease in receptor protein). This was apparently an internalization of the receptors, as the receptor mRNA (expression) remained unchanged.
In the stress-responsive rats, this downregulation was evident after 5 weeks. While the stress-sensitive rats showed no change in receptor mRNA expression, this increased in the stress-resistant rats after 5 weeks, so that the increase in expression had equalized the number of D2 receptors after 5 weeks. The stress-resilient rats thus showed a strong neurobiological plasticity of dopamine D2 receptor density and mRNA expression, in contrast to the stress-sensitive animals.¹⁴
Another study found no correlation between stress-related anhedonia and differences¹³

• in the ventral striatum
  • D1 expression
  • D2 expression
  • Enkephalin
  • Dynorphin
  • NMDA NR2B receptor
• in the dentate gyrus
  • BDNF Expression
• in the paraventricular nucleus of the hypothalamus to
  • CRH
  • Arginine / Vasopressin

Differences were found for anhedonia

• in CA3 of the ventral hippocampus:
  • Upregulation of BDNF mRNA in the stress-resilient group
  • Downregulation of VEGF mRNA (vascular endothelial growth factor) in the stress-sensitive group.

Furthermore, activation of the HPA axis was found in the stress-resistant rats.

Antidepressants increase D2 receptor expression, which may describe one element of their antidepressant effect.¹⁵

2.1.1.2. Upregulation¶

Upregulation is the same adaptation mechanism at work that attempts to compensate for long-term fluctuations in neurotransmitter or hormone levels. While downregulation is an adaptation to neurotransmitter/hormone levels that are too high, upregulation is the consequences of neurotransmitter/hormone levels that are too low. The receptor systems react to long-term low levels by increasing the number of receptors or sensitizing the receptors.

2.1.2. Non-specific, permanently increased excitability of nerve cells (basic principle)¶

As early as 1990, Aldenhoff described a model that could explain the development of increased excitation of nerve cells as a permanent pathological condition.
If a nerve cell is synaptically excited in a certain way (with a certain frequency), a longer-lasting potentiation of synaptic transmission can occur (long-term potentiation = LTP). If a ligand binds to the NMDA receptor (NMDA = N-methyl-D-aspartate) at the same time as membrane depolarization occurs, this leads to an above-average calcium current. Such excessive calcium currents cause the phosphorylation processes to take on a life of their own, which then proceed independently of calcium. This is the basic mechanism for the increase in synaptic transmission and is probably the basic function of learning processes.¹⁶

Hypercortisolism is an endocrine finding in many mental illnesses.¹⁷
In ADHD-I, we understand that there is a hypercortisol imbalance in the stress systems.

During stress, the stress hormone CRH is released in the hypothalamus. This has an excitatory effect on the cells of the hippocampus by reducing the calcium-dependent potassium conductivity.

2.1.2.1. Noradrenaline release decoupled from external stimuli¶

Increased doses of CRH over a longer period of time cause the excitatory effect to manifest itself permanently. This means that an increased level of cellular arousal is maintained regardless of the presence of CRH.¹⁸

The phasic activity of cells in the locus coeruleus, which serves attention, is a reaction to incoming external signal stimuli. These trigger a discharge in the locus coeruleus (noradrenaline release), which is followed by a pause in activity (in the interest of signal-to-noise ratio).
A higher amount of CRH initially increases excitability and thus the release of noradrenaline. However, a permanently increased amount of CRH decouples the release of noradrenaline from the phasic stimulus in the long term. Noradrenaline is then released independently of incoming stimuli. This leads to a deterioration in the signal-to-noise ratio, which can disrupt cognitive functions.¹⁹ The mechanism of downregulation is also likely to cause downregulation of the noradrenaline receptors (adrenoceptors) due to the permanently increased noradrenaline levels.

In addition, the stress-related release of noradrenaline increases with the frequency of a stressful experience. In the case of repeated stress experiences, the amount of norepinephrine released due to stress is higher than during the first stress experience.²⁰

2.1.2.2. CRH receptor downregulation reduces stress system inhibition and leads to non-specific excitability¶

CRH acts on the CRH receptors CRFR1 and CRFR2. A permanently excessive release of CRH and/or corticosteroids (cortisol) also leads to a reduction in these receptors (downregulation). This means that in addition to the permanently increased excitatory effect of CRH, there is also reduced inhibition due to the regression of the corticosteroid receptors. This leads to increased non-specific psychophysiological excitability.²¹

Severe stress completely abolishes the usual enhancing effect of CRF on DA release in the NAc for at least 90 days. This could be the biological substrate for the fact that traumatic or chronic stress can promote the onset of severe depression, in which an acute stressor is no longer perceived as motivating but as an insurmountable obstacle. Both CRH and DA regulate the emotional response to acute stressors.²² A loss of CRF regulation of DA release is accompanied by a switch in the response to CRH from appetitive to aversive²³.

2.1.3. Neurotoxic effects of stress hormones in chronic stress¶

2.1.3.1. Glucocorticoids (cortisol)¶

See also ⇒ Neurotoxic effects of glucocorticoids (cortisol) during prolonged stress In the article ⇒ Cortisol in the section ⇒ Hormones in ADHD in the chapter ⇒ Neurological aspects.

2.1.3.2. CRH¶

See also ⇒ Neurotoxic effects of CRH during prolonged stress In the article ⇒ CRH in the section ⇒ Hormones in ADHD in the chapter ⇒ Neurological aspects.

2.1.4. Altered gene expression due to chronic stress¶

Stress has different effects on one and the same gene depending on its duration. Short-term stress has a different effect than medium-term stress and long-term stress leads to different gene expressions.

• During stress, the catecholamine neurotransmitter systems are primarily affected. The TYH gene regulates tyrosine hydroxylase, which is produced in the adrenal glands and in the brain. Tyrosine hydroxylase (TYH) is the enzyme that catalyzes the conversion of the amino acid L-tyrosine into the amino acid levodopa, from which adrenaline, dopamine and noradrenaline are produced. This is therefore the rate-determining reaction step in the biosynthesis of catecholamines.²⁴
• Prolonged stress causes chronic demethylation of the CRH gene in adult mice.²⁵
• Depending on its duration, stress causes different transcription factors of the TYH gene to be addressed:
  • Short-term stress (3 minutes) causes the phosphorylation of CREB-1 and Jun
  • Medium stress (30 - 120 minutes) causes de novo synthesis of transcription factors such as c-fos and EGR1
  • Prolonged stress activates EGR1 and FRA2²⁶

The TYH gene is therefore expressed differently depending on the duration of the stress. This manifests itself in different gene activity, which changes the availability of adrenaline, dopamine and norrenaline.

2.1.5. Atrophy in various areas of the brain¶

Chronic unpredictable stress causes atrophy (tissue shrinkage) in several areas of the brain in rats:²⁷

• Different cortical areas
  • Prelimbic cortex
  • Cingulate cortex
  • Insular cortex
  • Retrosplenial cortex
  • Somatosensory cortex
  • Motor cortex
  • Auditory cortex
  • Perirhinalentorhinal cortex
• Hippocampus
• Dorsomedial striatum
• Nucleus accumbens
• Septum
• Bed nucleus of the stria terminalis
• Thalamus
• Several brainstem nuclei.

At the same time, functional connectivity within a network consisting of these regions is increased.

There were groups of high-stress responders and low-stress responders.²⁷

• High responders (stress-sensitive animals) showed local atrophy of the VTA and an increase in functional connectivity between this area and the thalamus and other brain regions that connect the cognitive system with the fight-or-flight system.
• High-stress responders and low-stress responders were further distinguished on the basis of functional connectivity in a network between the brainstem and the limbic system. These are thought to represent the first known potential imaging predictive biomarkers for an individual’s vulnerability to stress conditions.

2.1.6. Increased neuroinflammation due to chronic stress¶

In adults with ADHD, increased perceived chronic stress correlated linearly with increased inflammatory proteins.²⁸
There were two groups within the test group:

• one with a higher inflammatory potential
  • higher chronic stress (p < 0.001)
  • higher ADHD scores (p = 0.030)
  • higher risk of suicide (p = 0.032)
• one with a lower inflammatory potential

The most significant differences concerned (unaffected by ADHD medication, but influenced by concomitant psychotropic medication):

• NF-κB signaling pathway
• Chemokine signaling
• IL-17 signaling
• Metabolic changes
• Chemokine attraction

2.2. Concrete damage caused by chronic stress¶

2.2.1. Changes in the dopaminergic system due to early or chronic stress¶

This topic is described in detail in the article Dopamine and stress In the section Dopamine in the chapter Neurological aspects.

2.2.2. Increased ΔFosB in the reward circuits¶

ΔFosB (DeltaFosB) is a truncated form of the transcription factor FosB. ΔFosB is considered a molecular marker for chronic stimulation of the reward circuitry, stress-induced neuroplasticity and sensitization to psychostimulants.²⁹ Directly after singular stress, ΔFosB is barely detectable, but adds up significantly after repeated social stress or repeated drug administration due to its longevity. Chronic psychosocial stress also significantly increased the number of ΔFosB neurons in the PFC, nucleus accumbens and amygdala of rats for 3 weeks.³⁰³¹ Increased ΔFosB in the reward circuitry increases sensitivity to psychostimulants such as cocaine.³² ΔFosB regulates the expression of many neuroplasticity-related genes in the reward circuitry after chronic drug exposure.³³

2.2.3. Damage to the amygdala (increased anxiety)¶

2.2.3.1. Enlargement of the amygdala due to serine protease “tissue-plasminogen factor”¶

During long-term stress, the serine protease “tissue-plasminogen factor” is increasingly expressed in the amygdala. This leads to an enlargement of the amygdala, which causes increased anxiety.³⁴

It is empirically recognized that stress is a (co-)cause of anxiety and fear disorders (e.g. post-traumatic stress disorder, phobias, panic attacks, generalized anxiety disorder) and depression.³⁵

2.2.3.2. Amygdala neurons become hyperexcitable¶

Chronic stress causes the main output neurons of the basolateral amygdala to become hyperexcitable.³⁶
More on this above at ⇒ Nonspecific permanently increased excitability of nerve cells (basic principle).

2.2.4. Damage to the hippocampus (learning and memory disorders)¶

Chronic stress impairs the hippocampus.³⁷ Like the amygdala, the hippocampus is involved in controlling the HPA axis and thus in regulating the release of CRH.³⁸ Damage to the hippocampus therefore impairs the controllability of the HPA axis.³⁹⁴⁰⁴¹ The hippocampus primarily has an inhibitory effect on the HPA axis.

The hippocampus is one of the most sensitive and malleable regions of the brain and is very important for learning and memory processes. Within the hippocampus, signals are routed from the entorhinal cortex to the dentate gyrus through the connections between the dentate gyrus and the CA3 pyramidal neurons. A single neuron addresses an average of 12 CA3 neurons, with each CA3 neuron addressing an average of 50 additional CA3 neurons and 25 inhibitory cells via axon collaterals. This results in a 600-fold amplification of the excitation and a 300-fold amplification of the inhibition.⁴² The high signal amplification makes the hippocampus particularly susceptible.³⁵

A moderate increase in cortisol supports memory formation through increased excitation of the hippocampus. A strong increase in cortisol (as caused by stress-related activity of the HPA axis) disrupts these functions of the hippocampus.⁴³⁴⁴⁴⁵

Gonadal, thyroid and adrenal hormones modulate changes in synapse formation and in the dendritic structure of the hippocampus, which influences the volume of the dentate gyrus (part of the hippocampus) in childhood and adulthood.⁴²

Long-term elevated cortisol levels damage the hippocampus.⁴¹⁴⁶

2.2.4.1. Early prolonged stress experiences cause a smaller hippocampus in adults¶

Adults who suffered intense stressful experiences as children show a reduction in hippocampal volume.^47484950
The hippocampus is also smaller in children with early stress experiences.⁵¹⁵²

Hippocampal volume reductions in children due to early stress are more permanent than hippocampal volume reductions due to acute stress in adults.⁵³⁵⁴

Chronic stress due to immersion in water or immobilization causes neuronal degeneration of the hippocampus in rats.⁵⁵⁵⁶

2.2.4.2. Cell layer irregularities¶

Chronic cortisol administration caused cell layer irregularities in the hippocampus of primates.⁵⁷

2.2.4.3. Soma shrinkage and condensation¶

Chronic cortisol administration caused shrinkage and condensation of the cytosoma (cell body) in the hippocampus of primates.⁵⁷

2.2.4.4. Core pyknosis¶

Cortisol causes nuclear pyknosis in the hippocampus of primates (compaction of the chromatin in the cell nucleus and simultaneous shrinkage of the nuclear membrane).⁵⁷

2.2.4.5. Permanent stress reduces apical dendrite trees in the hippocampus¶

Prolonged massive stress causes a reduction in the size of the apical dendrite tree (dendrites: cell extensions of nerve cells) of pyramidal cells in the CA1 and CA3 regions of the hippocampus. As a result, the apical dendrite tree has fewer branches and a shorter overall length.⁵⁸⁴² This effect is mediated by cortisol.⁵⁷⁴⁶

If the activity of the hippocampal nerve cells is impaired due to the reduced size of the dendrites, this reduces the hippocampus’s ability to control stress.
This can lead to a vicious circle in which the increasingly poorly controlled stress leads to an ever greater and longer release of cortisol, which further impairs the hippocampus and reduces its stress control.³⁵

2.2.4.6. Long-term stress alters cell adhesion molecules in the hippocampus¶

Permanent stress alters cell adhesion molecules (immunoglobulin proteins) that are involved in the

• Development of the nervous system,
• Plastic changes in the brain,
• Participate in contact mediation between presynapse and postsynapse
  and which also
• Are signaling molecules.

Long-term stress reduces the transcription of the cell adhesion molecule NCAM-140, which causes the hippocampus to shrink.³⁵

2.2.4.7. Acute and chronic stress suppresses the neurogenesis of cells in the dentate gyrus of the hippocampus¶

Glucocorticoids (cortisol), excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors are involved in the impairment of neurogenesis of cells in the dentate gyrus (part of the hippocampus) and in neuronal death due to seizures and ischemia of cells in the dentate gyrus. The human hippocampus undergoes selective atrophy in a number of disorders, including those mentioned, supported by deficits in declarative, episodic, spatial and contextual memory. From a therapeutic point of view, it is important to distinguish between permanent cell loss and reversible atrophy.⁴⁹

2.2.4.8. Cortisol increases glutamate effect on NMDA receptors in the hippocampus¶

Cortisol increases the effect of the excitatory neurotransmitter glutamate on NMDA receptors. This firstly increases the calcium influx into hippocampal neurons and secondly influences the serotonin system of the hippocampus towards increased excitation.⁵⁸
This mechanism generally improves learning. However, if the cortisol load is too high or too long, the hippocampus is damaged.³⁵

2.2.4.9. Noradrenaline increased¶

Chronic stress caused by movement restriction in the hippocampus of rats:⁵⁹

• Noradrenaline increased by 104
• Noradrenaline transporter (NET) reduced by 16 %
• DBH (dopamine β-hydroxylase) increased by 30
• VMAT2 increased by 11
• BDNF increased by 11

Chronic immobilization stress Stress led first to an increase and subsequently to a loss of noradrenergic cells in the locus coeruleus:⁶⁰

• Locus coeruleus: alteration of noradrenergic cells
  • increase of 33 % on the first day (acute stress)
  • in the 2nd week increase by 8 % (from now on chronic stress)
  • loss of 6 % in the 4th week.
  • loss of 24 % in the 8th week.
  • loss of 30 % in the 16th week.

Consequences: Noradrenaline in the striatum increased by 80 % after 4 weeks and by 30 % after 8 weeks.

2.2.5. Changes in the PFC¶

Cortisol damages the PFC in the long term.⁶¹ As the PFC is involved in the inhibition of the HPA axis (stress axis), a long-lasting high cortisol level leads to an impairment of the inhibition of the HPA axis.⁶²⁶³ This is also a vicious circle.

2.2.5.1. Permanent stress reduces apical dendrite trees in the PFC¶

Prolonged stress causes a reduction in the size of neurons and dendrites in the PFC by triggering a pronounced and sustained ERK1/2 hyperphosphorylation in dendrites of the higher PFC layers (II and III) and a reduction in phospho-CREB expression in various cortical and subcortical regions.⁶⁴

2.2.5.2. Cortisol reorganizes dendrite trees in PFC and hippocampus¶

The changes in the dendrite trees in the PFC caused by prolonged high cortisol levels are similar to the changes in the hippocampus.⁶⁵

2.2.6. Changes in the BDNF system due to chronic stress¶

Repeated social stress leads to lifelong social phobia in mice due to:

• Excessive BDNF level in the VTA / nucleus accumbens pathway⁶⁶
• Reduced BDNF level in the hippocampus⁶⁷

In rats, episodic psychosocial stress (4 times in 10 days) caused an increase in BDNF in the VTA, while chronic 5-week psychosocial stress caused a flattened BDNF response.⁶⁸

2.2.7. Changes in the serotonergic system due to chronic stress¶

Repeated chronic stress in mice leads to changes in serotonin release in the dorsal raphe nuclei during acute stress. The resulting behavioral and functional adaptations to chronic stress appear to be mediated by regulatory changes in microRNA.⁶⁹

2.2.8. Changes in the cortisolergic system due to chronic stress¶

In addition to changes in the dopaminergic and noradrenergic systems, prolonged chronic stress also leads to changes in the cortisolergic system. Chronic stress is regularly accompanied by a reduced basal cortisol level⁷⁰ (mild tonic hypocortisolism). The schematic processes that lead to a breakdown of the cortisolergic system can be found at ⇒ Breakdown of the cortisol system over the stress phases In the article ⇒ The human stress system - the basics of stress in the chapter ⇒ Stress.

The basal cortisol level is also reduced in ADHD. This affects all ADHD subtypes.

2.2.9. Changes in the alloprenal system due to chronic stress¶

Acute stress increases allopregnanolone, which in turn inhibits the HPA axis (as does cortisol). Chronic stress, on the other hand, as it contributes to the development of neuropsychiatric disorders such as depression and anxiety, leads to a decrease in allopregnanolone levels, which impairs the ability to downregulate the HPA axis after its acute activation.⁷¹
The effect here corresponds to that of cortisol.

2.2.10. Changes in the circadian system due to chronic stress¶

Repeated stress leads to changes in the circadian rhythm. Only occasional stress has little effect on the clock system. Stress signals that occur more frequently desynchronize the various cell and tissue clocks in the body.⁷²⁷³

If the circadian rhythm (here: the daily cortisol level) is artificially leveled, this leads to a weakened deactivation of the HPA axis (at least of ACTH).⁷⁴⁷⁵
According to our understanding, ADHD-HI and ADHD-C are often characterized by shutdown problems of the HPA axis.

Disturbed or missing circadian patterns can lead to an unhealthy regulation of the HPA axis and thus contribute to allostatic load. Thus, both a disorder of the HPA axis and a disorder of circadian rhythms could have interacting effects and contribute to shifts in resilience and vulnerability.⁸²

In detail on stress and disorders of the circadian system: Wolf, Calabrese (2020).⁸³

2.2.11. Changes in energy storage in fat due to chronic stress¶

• Chronic stress causes³⁷
  • Storage of energy in visceral fat deposits through a combination of hypercortisolism and hyperinsulinemia
  • Suppression of the gonadal/growth hormone/thyroid axis.
  • Consequences:
    • Central obesity
    • Hypertension
    • Dyslipidemia
    • Endothelial dysfunction

2.3. Mechanisms of action of acute stress¶

Acute stress causes:

• Increased release of glucocorticoids³⁷
• Catecholamine release increases³⁷
  • Increased dopamine release in the brain^{8485 86 87 88}
    • Which is probably also mediated via the stress hormone CRH⁸⁹
    • Reduction of dopaminergic activity in the dorsal ventral tegmentum in adults due to stress⁹⁰
    • Increase in dopaminergic activity in the ventral part of the ventral tegmentum in adults⁹⁰
    • Increase in tonic⁹¹ and phasic⁹² dopamine in the nucleus accumbens during novel unavoidable/uncontrollable stress. In the case of chronic stress, tonic dopamine falls below the initial value until the stressor ends. This corresponds to the individual’s primary and secondary assessment of a stressor that cannot be eliminated.
      • These changes in tonic dopamine in the nucleus accumbens are controlled by the mPFC.⁹¹
      • Acute and repetitive stress activates the entire dopamine system, which particularly addresses the associative (dorsal) striatum, which is important for object acuity, whereas in chronic stress-induced depression the blunting of the dopamine response occurs mainly in the neurons projecting to the ventromedial striatum, where reward-related variables are processed⁹³
    • While electrophysiological studies concluded that aversive stimuli inhibit the activity of most dopaminergic VTA neurons and only increase dopaminergic activity in a small subset of dopaminergic VTA neurons, microdialysis studies showed that various stressors cause a robust dopaminergic increase in extracellular dopamine and its metabolites in the nucleus accumbens and mPFC, into which the ventral tegmentum projects. In acute (first-time) stress, the increase begins immediately in the nucleus accumbens, reaches its maximum after 30 to 40 minutes and returns to baseline after 70 to 80 minutes. In the case of repeated or chronic stress, the increase in the nucleus accumbens decreases to zero and then to a reduction in dopamine with a maximum within 80 to 120 minutes. In the mPFC, acute stress was followed by an increase in dopamine during the stress and a further increase after the end of the stressor. Early childhood stress (malnutrition during pregnancy) correlated with no increase in dopamine and a decrease in dopamine after the end of the stressor.⁹⁴
    • There may be (at least) two subsets of dopamine neurons in the VTA: one group that encodes reward prediction errors and is suppressed by aversive stimulation, and a second group with atypical Ih and high baseline burst firing that is stimulated phasically by aversive stimuli.⁹⁵
  • Even a single stressful experience not only increases the release of dopamine in the ventral tegmentum (VTA) once, but also increases the willingness of the dopaminergic cells in the VTA to release dopamine in the event of future stressful experiences. Thus, acute stress can alter the responsiveness of VTA dopamine neurons to future stressors or rewards.⁹⁴ This increase in dopaminergic responsiveness to subsequent stressful experiences does not occur if the glucocorticoid receptors are previously blocked.^96979899 The increase in dopaminergic reactivity to cocaine did not occur when the dopamine D1 receptor was blocked.⁹⁷
  • Dopamine release in the body increases¹⁰⁰
    • note: Dopamine cannot cross the blood-brain barrier. The peripheral dopamine system is therefore completely decoupled from the central dopamine system.
• Sympathetic nervous system activated³⁷

• Inhibition of the hypothalamic-pituitary axis and thus of reproduction¹⁰¹

• Insulin resistance in the liver³⁷
• Insulin resistance in the skeletal muscles³⁷
• Microglia activation⁵
  A single 8-hour immobility stress altered the morphology of microglial cells towards more intense and larger cell bodies in substantia nigra and locus coeruleus. This response of microglia persisted even after 16 weeks of chronic stress. The inflammation levels could be detected by increased iNOS protein expression.

Intermittent acute tail shock stress increased extracellular dopamine in rats by 25% in the striatum, 39% in the nucleus accumbens and 95% in the medial frontal cortex compared to baseline.⁸⁷ Overstimulation of the dopamine D1 receptor in the PFC impairs working memory.¹⁰² The PFC requires balanced dopamine levels for optimal function.¹⁰²¹⁰³

50 or 100 uncontrollable tail current shocks were induced in rats:¹⁰⁴

• a reduction in physical activity in the mouse wheel by 50 % or 75 % within the following 9 weeks
• a reduction in the physical activity-induced increase in dopamine turnover in the PFC and hippocampus and increased serotonin turnover in the hypothalamus and rest of the cortex
• a slight dopamine deficiency in the striatum, which could explain the reduced motivation for physical activity
• increased HSP70 protein concentrations in the gastrocnemius muscle, which could indicate persistent oxidative stress.
• decreased SOD2 protein concentrations in the gastrocnemius muscle, which could indicate persistent oxidative stress.

2.4. Different Consequences of Acute and Chronic Stress¶

2.4.1. Consequences of acute stress¶

Acute stress can be a trigger:¹⁰⁵

• Allergic symptoms, such as
  • Asthma
  • Eczema
  • Urticaria
• Angiokinetic phenomena, such as
  • Migraine

• hypertensive or hypotensive seizures
• Pain, like
  • Headache
  • Abdominal pain
  • Pelvic pain
  • Back pain
• gastrointestinal symptoms such as
  • Pain
  • Digestive disorders
  • Diarrhea
  • Constipation
• Panic attacks
• psychotic episodes

2.4.2. Consequences of chronic stress¶

Chronic stress can be a trigger:¹⁰⁵

• Physical manifestations
  • Cardiovascular cardiovascular phenomena, such as
    • High blood pressure
  • Atherosclerotic cardiovascular cardiovascular diseases
  • Neurovascular degenerative diseases
  • Osteopenia / osteoporosis
  • Metabolic disorders, such as
    • Obesity
    • Metabolic syndrome
    • Type 2 diabetes mellitus
• Behavioral and/or neuropsychiatric manifestations
  • Fear
  • Depression,
  • Executive and/or cognitive dysfunction
  • Sleep disorders such as
    • Insomnia
    • Excessive daytime tiredness