Dear reader of, please excuse the disruption. needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find useful, please take a minute and support with your donation. Thank you!

Since 01.06.2021 is supported by the non-profit ADxS e.V..

$18094 of $63500 - as of 2024-04-30
Header Image
2. Stress by duration: long-lasting, chronic stress

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

Here we present studies on the harmfulness of long-term (chronic) stress that are not based on the age of those affected. 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.

Permanent 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 As a result, the dopamine level in the striatum decreased by around 40 % in weeks 4 and 8. Serotonin was reduced by 25 % in the striatum after 4 weeks and by 15 % after 8 weeks.
Against this background, it is hardly surprising that chronic stress causes very similar symptoms to ADHD, which is also characterized by a lack of dopamine.

Chronic stress can reduce the sensitivity of receptors (downregulation). The desensitization of cortisol receptors leads to impaired stress regulation and is associated with ADHD. Further consequences of chronic stress are 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 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 stages, 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.

Unfortunately, there is no evidence that withdrawal from stress could lead to the regeneration of the stress regulation systems damaged in ADHD. This is also not particularly likely, as ADHD is generally not the result of chronic stress, but an effect of certain gene variants that reduce dopamine and noradrenaline levels in the same way as chronic stress does.

ADHD could also be described externally as extreme hypersensitivity of the stress systems. Nevertheless, even very extensive stress withdrawal is unlikely to be able to take place in such a way that appropriate participation in life remains possible. Preventing a person from ever experiencing stress again is almost impossible - and in some ways nonsensical. After all, stress is a fundamentally very healthy reaction (see: stress benefits).

Furthermore, ADHD genes and additional chronic stress can together cause an increase in symptoms. A subclinical ADHD that reaches the severity of an ADHD disorder due to the addition of chronic stress would be conceivable. This picture is consistent with reports that the successful treatment of comorbid rhinitis in ADHD sufferers could significantly improve ADHD symptoms, or that the elimination of a food intolerance through an appropriate diet had the same effect. This may also be a key to understanding late onset ADHD.

In any case, developing an awareness that chronic stress is their worst enemy should certainly be therapeutically helpful for ADHD sufferers. Acute stress, on the other hand - in the right doses - can certainly be helpful.

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 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 As a result, 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 according to 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 key to the future treatment of ADHD. Downregulation in chronic stress: glutamate receptors in the mPFC

Chronic unpredictable stress leads to a deregulation of the glutamate balance in mice, resulting in 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. 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 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 excessively high neurotransmitter/hormone levels, upregulation is the result of excessively low neurotransmitter/hormone levels. 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 take place 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 hippocampal cells by reducing the calcium-dependent potassium conductivity. 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 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 may be the biological substrate for the fact that traumatic or chronic stress can promote the onset of major 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 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. 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 values (p = 0.030)
    • higher risk of suicide (p = 0.032)
  • one with a lower inflammatory potential

The most significant differences were (unaffected by ADHD medication, but affected 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. Alteration of 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 considerably due to its longevity after repeated social stress or repeated drug administration. 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) 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 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 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 Cell layer irregularities

Chronic cortisol administration caused cell layer irregularities in the hippocampus of primates.57 Soma shrinkage and condensation

Chronic cortisol administration caused shrinkage and condensation of the cytosoma (cell body) in the hippocampus of primates.57 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 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 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 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, accompanied by deficits in declarative, episodic, spatial and contextual memory performance. From a therapeutic point of view, it is important to distinguish between permanent cell loss and reversible atrophy.49 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 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 first led 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.

As a result, 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. 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 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, long-term 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 of how the cortisolergic system breaks down 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 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.7172

If the circadian rhythm (here: the daily cortisol level) is artificially leveled, this leads to a weakened shutdown of the HPA axis (at least of ACTH).7374
According to our understanding, ADHD-HI and ADHD-C are often characterized by shutdown problems of the HPA axis.

Cortisol is also able to reset peripheral oscillators in other body tissues:73
There appears to be an important relationship between disrupted circadian rhythms and allostatic load.7576 The master circadian clock in the SCN of the hypothalamus controls all circadian rhythms in physiology and behavior.77 In addition, “peripheral” circadian clocks throughout the body serve to set local time. These peripheral clocks are synchronized with the SCN by a variety of signals (including glucocorticoids). Glucocorticoids are able to “reset” some (but not all) peripheral clocks in the brain and body (e.g. in the liver).78
The rhythms of glucocorticoids modulate the expression of clock proteins in the oval nucleus of the bed nucleus of the stria terminalis and in the central amygdala.79 In contrast, the basolateral nuclei of the amygdala and the dentate gyrus of the hippocampus express diurnal rhythms of PERIOD2 (a central clock component) that are opposite to those of the central amygdala. An adrenalectomy (removal of the adrenal gland, in whose cortex, among other things, cortisol is synthesized) influences the rhythm of the central amygdala.80

Disturbed or missing circadian patterns can lead to an unhealthy regulation of the HPA axis and thus contribute to allostatic load. Thus, both a disruption of the HPA axis and a disruption of circadian rhythms could have interacting effects and contribute to shifts in resilience and vulnerability.81

In detail on stress and disorders of the circadian system: Wolf, Calabrese (2020).82

2.2.10. 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
    • Dopamine release in the brain increases8384 85 86 87
      • Which is probably also mediated via the stress hormone CRH88
      • Reduction of dopaminergic activity in the dorsal ventral tegmentum in adults due to stress89
      • Increase in dopaminergic activity in the ventral part of the ventral tegmentum in adults89
      • Increase in tonic90 and phasic91 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.90
        • Acute and repeated 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 processed92
      • 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 of extracellular dopamine and its metabolites in the nucleus accumbens and mPFC, where 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.93
      • 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.94
    • 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.93 This increase in dopaminergic responsiveness to subsequent stressful experiences does not occur if the glucocorticoid receptors are previously blocked.95969798 The increase in dopaminergic responsiveness to cocaine did not occur when the dopamine D1 receptor was blocked.96
    • Dopamine release in the body increases99
      • 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 reproduction100
  • Insulin resistance in the liver37
  • Insulin resistance in the skeletal muscles37
  • Microglia activation5
    A single 8-hour immobility stress changed 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.86 Overstimulation of the dopamine D1 receptor in the PFC impairs working memory.101 The PFC requires balanced dopamine levels for optimal function.101102

50 or 100 uncontrollable tail current shocks were induced in rats:103

  • 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:104

  • 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:104

  • 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

  1. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 115

  2. Bremner JD. Long-term eff ects of childhood abuse on brain and neurobiology. Child Adolesc Psychiatr Clin North Am 2003; 12: 271–92.

  3. Gresch, Sved, Zigmond, Finlay (1994): Stress-induced sensitization of dopamine and norepinephrine efflux in medial prefrontal cortex of the rat. J Neurochem. 1994 Aug;63(2):575-83.

  4. Morrow, Redmond, Roth, Elsworth (2000): The predator odor, TMT, displays a unique, stress-like pattern of dopaminergic and endocrinological activation in the rat. Brain Res. 2000 May 2;864(1):146-51.

  5. Sugama, Kakinuma (2016): Loss of dopaminergic neurons occurs in the ventral tegmental area and hypothalamus of rats following chronic stress: Possible pathogenetic loci for depression involved in Parkinson’s disease. Neurosci Res. 2016 Oct;111:48-55. doi: 10.1016/j.neures.2016.04.008. PMID: 27142317.

  6. am Beispiel der GABA-Rezeptoren: Bäckstrom, Birzniece, Fernandez, Johansson, Kask, Lindblad, Lundgren, Hyberg, Ragagnin, Sundström-Poromaa, Strömberg, Turkman, Wang, von Boekhoven, van Wingen: Neuroactive Steroids: Effects on Cognitive Functions; in: Weizman (Herausgeber) (2008): Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment; Chapter 5, S 103 ff

  7. Miller, Ancoli-Israel, Bower, Capuron, Irwin (2008): Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer; J Clin Oncol. 2008 Feb 20; 26(6): 971–982. doi: 10.1200/JCO.2007.10.7805, PMCID: PMC2770012, NIHMSID: NIHMS147295

  8. Wang, Wu, Miller (2004): Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry. 2004 Jan;9(1):65-75.

  9. Pace, Hu, Miller (2007): Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun. 2007 Jan;21(1):9-19.

  10. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seiten 120, 151

  11. Holsboer (2001): Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord. 2001 Jan;62(1-2):77-91.

  12. Jett, Bulin, Hatherall, McCartney, Morilak (2017): Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex. Neuroscience. 2017 Mar 27;346:284-297. doi: 10.1016/j.neuroscience.2017.01.017.

  13. Bergström, Jayatissa, Mørk, Wiborg (2008): Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study. Brain Res. 2008 Feb 27;1196:41-52. doi: 10.1016/j.brainres.2007.12.025. PMID: 18234161.

  14. Zurawek, Faron-Górecka, Kuśmider, Kolasa, Gruca, Papp, Dziedzicka-Wasylewska (2013): Mesolimbic dopamine D₂ receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress. Psychopharmacology (Berl). 2013 Jun;227(4):583-93. doi: 10.1007/s00213-013-2990-3. PMID: 23377023; PMCID: PMC3663201.

  15. Gershon, Vishne, Grunhaus (2007): Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry. 2007 Jan 15;61(2):145-53. doi: 10.1016/j.biopsych.2006.05.031. PMID: 16934770. REVIEW

  16. Brown, Chapman, Kairiss, Keenan (1988): Long-term synaptic potentation. Science 242:724-728, zitiert nach Aldenhoff (1990): Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen, in: Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 183

  17. APA Task Force on Laboratory Tests on Psychiatry (1987): The dexamethasone suppression test: An overview of its current status in psychiatry, AM J Psychiatry 144, 1253-1262, zitiert nach Aldenhoff (1990): Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen, in: Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 184

  18. Aldenhoff (1990): Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen, in: Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 183

  19. Aldenhoff, Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen (1990) in Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 183

  20. Thierry, Javoy, Glowinski, Kety (1968): Effects of stress on the metabolism of norepinephrine, dopamine and serotonin in the central nervous system of the rat. I. Modifications of norepinephrine turnover. J Pharmacol Exp Ther. 1968 Sep;163(1):163-71. PMID: 5673703

  21. Aldenhoff (1990): Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen, in: Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 185 unter Verweis auf Aldenhoff (1989): Imbalance of neuronal excitability as a possible cause of psychic disorder; Pharmacopsychiatry 22:222-240

  22. Sulzer D, Cragg SJ, Rice ME (2016): Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016 Aug;6(3):123-148. doi: 10.1016/j.baga.2016.02.001. PMID: 27141430; PMCID: PMC4850498.

  23. Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE (2012): Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature. 2012 Oct 18;490(7420):402-6. doi: 10.1038/nature11436. PMID: 22992525; PMCID: PMC3475726.


  25. Elliott, Gili, Limor, Neufeld-Cohen (2010): Resilience to social stress coincides with functional DANN methylation of the CRF gene in adult mice. Nat Neurosci 2010; 13: 1351–53.

  26. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 134

  27. Magalhães, Barrière, Novais, Marques, Marques, Cerqueira, Sousa, Cachia, Boumezbeur, Bottlaender, Jay, Mériaux, Sousa (2018): The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome. Mol Psychiatry. 2018 Oct;23(10):1998-2006. doi: 10.1038/mp.2017.244.

  28. Schnorr I, Siegl A, Luckhardt S, Wenz S, Friedrichsen H, El Jomaa H, Steinmann A, Kilencz T, Arteaga-Henríquez G, Ramos-Sayalero C, Ibanez-Jimenez P, Rosales-Ortiz SK, Bitter I, Fadeuilhe C, Ferrer M, Lavebratt C, Réthelyi JM, Richarte V, Rommelse N, Ramos-Quiroga JA, Arias-Vasquez A, Resch E, Reif A, Matura S, Schiweck C. Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome. Transl Psychiatry. 2024 Jan 18;14(1):37. doi: 10.1038/s41398-023-02729-3. PMID: 38238292; PMCID: PMC10796401.

  29. Wang, Fanous, Terwilliger, Bass, Hammer, Nikulina (2013): BDNF overexpression in the ventral tegmental area prolongs social defeat stress-induced cross-sensitization to amphetamine and increases ΔFosB expression in mesocorticolimbic regions of rats. Neuropsychopharmacology. 2013 Oct;38(11):2286-96. doi: 10.1038/npp.2013.130. PMID: 23689674; PMCID: PMC3773680.

  30. Nikulina, Arrillaga-Romany, Miczek, Hammer (2008): Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of mu-opioid receptor mRNA and FosB/DeltaFosB immunoreactivity. Eur J Neurosci. 2008 May;27(9):2272-84. doi: 10.1111/j.1460-9568.2008.06176.x. PMID: 18445218; PMCID: PMC2442756.

  31. Perrotti, Hadeishi, Ulery, Barrot, Monteggia, Duman, Nestler (2004): Induction of deltaFosB in reward-related brain structures after chronic stress. J Neurosci. 2004 Nov 24;24(47):10594-602. doi: 10.1523/JNEUROSCI.2542-04.2004. PMID: 15564575; PMCID: PMC6730117.

  32. Kelz, Chen, Carlezon, Whisler, Gilden, Beckmann, Steffen, Zhang, Marotti, Self, Tkatch, Baranauskas, Surmeier, Neve, Duman, Picciotto, Nestler (1999): Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature. 1999 Sep 16;401(6750):272-6. doi: 10.1038/45790. PMID: 10499584.

  33. McClung, Ulery, Perrotti, Zachariou, Berton, Nestler (2004): DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res. 2004 Dec 20;132(2):146-54. doi: 10.1016/j.molbrainres.2004.05.014. PMID: 15582154.

  34. Pawlak, Magarinos, Melchor, McEwen, Strickland (2003): Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci. 2003 Feb;6(2):168-74.

  35. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 117

  36. Sharp (2017): Basolateral amygdala and stress-induced hyperexcitability affect motivated behaviors and addiction. Transl Psychiatry. 2017 Aug 8;7(8):e1194. doi: 10.1038/tp.2017.161. PMID: 28786979; PMCID: PMC5611728.

  37. Tsatsoulis, Fountoulakis (2006): The protective role of exercise on stress system dysregulation and comorbidities. Ann N Y Acad Sci. 2006 Nov;1083:196-213.

  38. Trapp, Holzboer (2013): Molekulare Mechanismen der Glucocorticoidtherapie; in: Ganten, Ruckpaul (2013): Erkrankungen des Zentralnervensystems, Springer, Seite 104

  39. Herman, Schäfer, Young, Thompson, Douglas, Watson (1989): Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis. J Neurosci 9:3072–3082

  40. Herman, Prewitt, Cullinan (1996): Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis. Crit Rev Neurobiol 10:371–394

  41. Nestler, Barrot, Dileone, Eisch, Gold, Monteggia (2002): Neurobiology of depression. Neuron 2002; 34: 13–25

  42. McEwen (1999): Stress and hippocampal plasticity.; Annu Rev Neurosci. 1999;22:105-22.

  43. Diamond, Bennett, Fleshner, Rose (1992): Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2, 421–43010.1002/hipo.450020409

  44. Pavlides, Watanabe, McEwen (1993): Effects of glucocorticoids on hippocampal long-term potentiation. Hippocampus 3, 183–19210.1002/hipo.450030210

  45. Pavlides, Kimura, Magarinos, McEwen (1994): Type I adrenal steroid receptors prolong hippocampal long-term potentiation. Neuroreport 5, 2673–267710.1097/00001756-199412000-00067

  46. Sapolsky (1985): A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 5:1228–1232

  47. Bei Depression: Vythilingam, Heim, Newport, Miller, Anderson, Bronen, Brummer, Staib, Vermetten, Charney, Nemeroff, Bremner (2002): Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry 2002; 159: 2072–80.

  48. Buss, Lord, Wadiwalla, Hellhammer, Lupien, Meaney, Pruessner (2007): Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. J Neurosci 2007; 27: 2592–5.

  49. McEwen (1999): Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105-22.

  50. McEwen (2007): Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007 Jul;87(3):873-904.

  51. Tottenham, Sheridan (2009): A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Front Hum Neurosci 2009; 3: 68., dort unter “Hippocampus und Stress”; entgegen Zitierung durch Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 50, die diese Quelle entgegen unserer Wahrnehmung als Stimme für keine verkleinerte Hippocampusvolumen bei früh stressbelasteten Kindern zitieren

  52. anders angeblich De Bellis, Keshavan, Spencer, Hall (2000): N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am J Psychiatry 2000; 157: 1175–7., zitiert nach Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 50

  53. Tottenham, Sheridan (2009): A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Front Hum Neurosci 2009; 3: 68., dort unter “Hippocampus und Stress”

  54. Seckl, Meaney (2004): Glucocorticoid programming. Ann N Y Acad Sci. 2004 Dec;1032:63-84.

  55. Mizoguchi, Kunishita, Chui, Tabira (1992): Stress induces neuronal death in the hippocampus of castrated rats. Neurosci Lett. 1992;138(1):157-160. doi:10.1016/0304-3940(92)90495-s

  56. Watanabe, Gould, McEwen (1992): Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588(2):341-345. doi:10.1016/0006-8993(92)91597-8

  57. Sapolsky, Uno, Rebert, Finch (1990): Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 10:2897–2902

  58. McKittrick, Magarinos, Blanchard, Blanchard, McEwen, Sakai (2000): Chronoc social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites.cSynapse. 2000 May;36(2):85-94. PMID: 10767055 DOI: 10.1002/(SICI)1098-2396(200005)36:2<85::AID-SYN1>3.0.CO;2-Y

  59. Gavrilović, Popović, Stojiljković, Pejić, Todorović, Pavlović, Pajović (2020): Changes of Hippocampal Noradrenergic Capacity in Stress Condition. Folia Biol (Praha). 2020;66(2):81-84. PMID: 32851838.

  60. Sugama, Sekiyama, Kodama, Takamatsu, Takenouchi, Hashimoto, Bruno, Kakinuma (2017): Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson’s disease. Brain Behav Immun. 2016 Jan;51:39-46. doi: 10.1016/j.bbi.2015.08.015. Erratum in: Brain Behav Immun. 2017 Mar;61:389. PMID: 26291405; PMCID: PMC4849407.

  61. Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 45

  62. Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 44

  63. Steckler, Kalin, Reul (2005): Handbook of Stress and the Brain, Teil 1; Elsevier, Seite 809

  64. Trentani, Kuipers, Ter Horst, Boer (2004): Selective chronic stress-induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress-related cortical pathology? European Journal of Neuroscience, 15: 1681–1691. doi:10.1046/j.1460-9568.2002.02000.x

  65. Wellman (2001), zitiert nach Steckler, Kalin, Reul (2005): Handbook of Stress and the Brain, Teil 1; Elsevier, Seite 809

  66. Berton, McClung, Dileone, Krishnan, Renthal, Russo, Graham, Tsankova, Bolanos, Rios, Monteggia, Self, Nestler (2006): Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006 Feb 10;311(5762):864-8. doi: 10.1126/science.1120972. PMID: 16469931.

  67. Duman, Deyama, Fogaça (2021): Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci. 2021 Jan;53(1):126-139. doi: 10.1111/ejn.14630. PMID: 31811669; PMCID: PMC7274898. REVIEW

  68. Miczek KA, Nikulina EM, Shimamoto A, Covington HE 3rd. Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats. Version 2. J Neurosci. 2011 Jul 6;31(27):9848-57. doi: 10.1523/JNEUROSCI.0637-11.2011. PMID: 21734276; PMCID: PMC3144494.

  69. Babicola, Pietrosanto, Ielpo, Luca D’Addario, Cabib, Ventura, Ferlazzo, Helmer-Citterich, Andolina, Lo Iacono (2020): RISC RNA sequencing in the Dorsal Raphè reveals microRNAs regulatory activities associated with behavioral and functional adaptations to chronic stress. Brain Res. 2020 Mar 10:146763. doi: 10.1016/j.brainres.2020.146763. PMID: 32169579.

  70. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie, S. 205

  71. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie, S. 199

  72. Albrecht (2019): Molecular Connections Between Circadian Clocks and Mood-related Behaviors. J Mol Biol. 2020 May 29;432(12):3714-3721. doi: 10.1016/j.jmb.2019.11.021. PMID: 31863752. REVIEW

  73. McEwen, Karatsoreos (2015): Sleep Deprivation and Circadian Disruption: Stress, Allostasis, and Allostatic Load. Sleep Med Clin. 2015 Mar;10(1):1-10. doi: 10.1016/j.jsmc.2014.11.007. PMID: 26055668. REVIEW

  74. Jacobson, Akana, Cascio, Shinsako, Dallman (1988): Circadian variations in plasma corticosterone permit normal termination of adrenocorticotropin responses to stress. Endocrinology. 1988 Apr;122(4):1343-8. doi: 10.1210/endo-122-4-1343. PMID: 2831028.

  75. Boivin, Tremblay, James (2007): Working on atypical schedules. Sleep Med. 2007 Sep;8(6):578-89. doi: 10.1016/j.sleep.2007.03.015. Epub 2007 May 3. PMID: 17481949. REVIEW

  76. Knutsson (2003): Health disorders of shift workers. Occup Med (Lond). 2003 Mar;53(2):103-8. doi: 10.1093/occmed/kqg048. PMID: 12637594. REVIEW

  77. Moore-Ede (1986): Physiology of the circadian timing system: predictive versus reactive homeostasis. Am J Physiol. 1986 May;250(5 Pt 2):R737-52. doi: 10.1152/ajpregu.1986.250.5.R737. PMID: 3706563.

  78. Balsalobre, Brown, Marcacci, Tronche, Kellendonk, Reichardt, Schütz, Schibler (2000): Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 2000 Sep 29;289(5488):2344-7. doi: 10.1126/science.289.5488.2344. PMID: 11009419.

  79. Segall, Perrin, Walker, Stewart, Amir (2006): Glucocorticoid rhythms control the rhythm of expression of the clock protein, Period2, in oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats. Neuroscience. 2006 Jul 7;140(3):753-7. doi: 10.1016/j.neuroscience.2006.03.037. PMID: 16678973.

  80. Lamont, Robinson, Stewart, Amir (2005): The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4180-4. doi: 10.1073/pnas.0500901102. PMID: 15746242; PMCID: PMC554834.

  81. Karatsoreos, McEwen (2011): Psychobiological allostasis: resistance, resilience and vulnerability. Trends Cogn Sci. 2011 Dec;15(12):576-84. doi: 10.1016/j.tics.2011.10.005. PMID: 22078931. REVIEW

  82. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie, S. 195 ff

  83. Wand, Oswald, McCaul, Wong, Johnson, Zhou, Kuwabara, Kumar (2007): Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress. Neuropsychopharmacology. 2007 Nov;32(11):2310-20. doi: 10.1038/sj.npp.1301373. PMID: 17342167.

  84. Imperato, Puglisi-Allegra, Casolini, Zocchi, Angelucci (1989): Stress-induced enhancement of dopamine and acetylcholine release in limbic structures: role of corticosterone. Eur J Pharmacol. 1989 Jun 20;165(2-3):337-8. doi: 10.1016/0014-2999(89)90735-8. PMID: 2776836.

  85. Zweifel, Fadok, Argilli, Garelick, Jones, Dickerson, Allen, Mizumori, Bonci, Palmiter (2011): Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci. 2011 May;14(5):620-6. doi: 10.1038/nn.2808. PMID: 21499253; PMCID: PMC3083461.

  86. Abercrombie, Keefe, DiFrischia, Zigmond (1989): Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem. 1989;52(5):1655-1658. doi:10.1111/j.1471-4159.1989.tb09224.x

  87. Gresch, Sved, Zigmond, Finlay (1994): Stress-induced sensitization of dopamine and norepinephrine efflux in medial prefrontal cortex of the rat. J Neurochem. 1994;63(2):575-583. doi:10.1046/j.1471-4159.1994.63020575.x

  88. Payer, Williams, Mansouri, Stevanovski, Nakajima, Le Foll, Kish, Houle, Mizrahi, George, George, Boileau (2017): Corticotropin-releasing hormone and dopamine release in healthy individuals. Psychoneuroendocrinology. 2017 Feb;76:192-196. doi: 10.1016/j.psyneuen.2016.11.034. PMID: 27951520.

  89. Brischoux, Chakraborty, Brierley, Ungless (2009): Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4894-9. doi: 10.1073/pnas.0811507106. PMID: 19261850; PMCID: PMC2660746.

  90. Cabib, Puglisi-Allegra (2011): The mesoaccumbens dopamine in coping with stress. Neurosci Biobehav Rev. 2012 Jan;36(1):79-89. doi: 10.1016/j.neubiorev.2011.04.012. PMID: 21565217. REVIEW

  91. Wenzel, Rauscher, Cheer, Oleson (2015): A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature. ACS Chem Neurosci. 2015 Jan 21;6(1):16-26. doi: 10.1021/cn500255p. PMID: 25491156; PMCID: PMC5820768. REVIEW

  92. Bloomfield, McCutcheon, Kempton, Freeman, Howes (2019): The effects of psychosocial stress on dopaminergic function and the acute stress response. Elife. 2019 Nov 12;8:e46797. doi: 10.7554/eLife.46797. PMID: 31711569; PMCID: PMC6850765.

  93. Holly, Miczek (2016): Ventral tegmental area dopamine revisited: effects of acute and repeated stress. Psychopharmacology (Berl). 2016 Jan;233(2):163-86. doi: 10.1007/s00213-015-4151-3. Epub 2015 Dec 17. PMID: 26676983; PMCID: PMC4703498. REVIEW

  94. Ungless , Argilli, Bonci (2010): Effects of stress and aversion on dopamine neurons: implications for addiction. Neurosci Biobehav Rev. 2010 Nov;35(2):151-6. doi: 10.1016/j.neubiorev.2010.04.006. PMID: 20438754.

  95. Saal, Dong, Bonci, Malenka (2003): Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003 Feb 20;37(4):577-82. doi: 10.1016/s0896-6273(03)00021-7. Erratum in: Neuron. 2003 Apr 24;38(2):359. PMID: 12597856.

  96. Dong, Saal, Thomas, Faust, Bonci, Robinson, Malenka (2004): Cocaine-induced potentiation of synaptic strength in dopamine neurons: behavioral correlates in GluRA(-/-) mice. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14282-7. doi: 10.1073/pnas.0401553101. PMID: 15375209; PMCID: PMC521147.

  97. Graziane, Polter, Briand, Pierce, Kauer (2013): Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron. 2013 Mar 6;77(5):942-54. doi: 10.1016/j.neuron.2012.12.034. PMID: 23473323; PMCID: PMC3632376.

  98. Niehaus, Murali, Kauer (2010): Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area. Eur J Neurosci. 2010 Jul;32(1):108-17. doi: 10.1111/j.1460-9568.2010.07256.x. PMID: 20608969; PMCID: PMC2908505.

  99. Ben-Jonathan (2020): Dopamine - Endocrine and Oncogenic Functions, S. 94

  100. Ben-Jonathan (2020): Dopamine - Endocrine and Oncogenic Functions, S. 97

  101. Zahrt, Taylor, Mathew, Arnsten (1997): Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci. 1997;17(21):8528-8535. doi:10.1523/JNEUROSCI.17-21-08528.1997

  102. Arnsten, Goldman-Rakic (1998): Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry. 1998;55(4):362-368. doi:10.1001/archpsyc.55.4.362

  103. Buhr TJ, Reed CH, Wee OM, Lee JH, Yuan LL, Fleshner M, Valentine RJ, Clark PJ (2023): The persistence of stress-induced physical inactivity in rats: an investigation of central monoamine neurotransmitters and skeletal muscle oxidative stress. Front Behav Neurosci. 2023 May 16;17:1169151. doi: 10.3389/fnbeh.2023.1169151. PMID: 37273279; PMCID: PMC10237271.

  104. Chrousos (2009): Stress and disorders of the stress system. Nat Rev Endocrinol. 2009 Jul;5(7):374-81. doi: 10.1038/nrendo.2009.106. PMID: 19488073. REVIEW