2. Stress by duration: long-lasting, chronic stress.
Here we present studies on the harmfulness of long-term stress that do not focus on the age of the affected person. 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 shows other damage patterns.
Acute (short-term) stress increases dopamine levels in the PFC.34
Chronic severe stress, on the other hand, decreased the level of dopamine in the PFC3 and resulted in a loss of dopaminergic cells in the hypothalamus, VTA, and substantia nigra, as well as a loss of noradrenergic cells in the locus coeruleus.5 As a result, dopamine levels in the striatum decreased by approximately 40% at weeks 4 and 8. Serotonin was decreased in the striatum by 25% at 4 weeks and 15% at 8 weeks.
Against this background, it is hardly surprising that chronic stress causes very similar symptoms to ADHD, which is also characterized by dopamine deficiency.
2.1. Damage mechanisms of chronic stress
2.1.1. Downregulation / Upregulation
- 126.96.36.199. Downregulation (receptor desensitization): Basic principle
- 188.8.131.52. Upregulation
- 2.1.2. Non-specific, permanently increased excitability of nerve cells (basic principle)
- 2.1.3. Neurotoxic effects of stress hormones in chronic stress
- 2.1.4. Altered gene expressions due to chronic stress
- 2.1.5. Atrophy in different brain areas
- 2.1.1. Downregulation / Upregulation
2.2. Concrete damage caused by chronic stress
- 2.2.1. Alteration of 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)
2.2.4. Damage to the hippocampus (learning and memory disorders)
- 184.108.40.206. Early prolonged stress experiences cause reduced hippocampus size in adults
- 220.127.116.11. Cell layer irregularities
- 18.104.22.168. Soma shrinkage and condensation
- 2.24.4. Core pyknosis
- 22.214.171.124. Prolonged stress reduces apical dendritic trees in the hippocampus
- 126.96.36.199. Prolonged stress alters cell adhesion molecules in the hippocampus
- 188.8.131.52. Acute as well as chronic stress suppresses neurogenesis of cells in the dentate gyrus of the hippocampus
- 184.108.40.206. Cortisol enhances glutamate action at NMDA receptors in the hippocampus
- 220.127.116.11. Norepinephrine increased
- 2.2.5. Changes in the PFC
- 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 of the circadian system due to chronic stress
- 2.2.10. 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
2.1. Damage mechanisms of chronic stress
2.1.1. Downregulation / Upregulation
18.104.22.168. Downregulation (receptor desensitization): Basic principle
Neurotransmitter systems are there to transmit signals in the brain. If the neurotransmitter level is optimal, signal transmission also functions optimally. A neurotransmitter level that is too low interferes with signal transmission in much the same way as a neurotransmitter level that is too high.
Neurotransmitters are released into the synaptic cleft by the sending neuron (presynapse) and taken up there by receptors of the receiving synapse (postsynapse). The neurotransmitter is then released back into the synaptic cleft by the receiving synapse and reabsorbed by the sending synapse via the transporters, where it is stored in the vesicles until its 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).
By means of down- (or up-) regulation, the body counteracts excessive (or reduced) levels of a messenger substance.
Downregulation occurs in several stages, one after the other, depending on the intensity and duration of neurotransmitter oversupply.6
- Receptor internalization
- Receptor regression
- Change in receptor mRNA expression (epigenetic change in gene expression)
This happens comparably with nicotine, alcohol or drug abuse. Withdrawal then causes withdrawal symptoms because the desensitized receptors now receive too little of the respective (now no longer artificially increased) neurotransmitters. After a few weeks of withdrawal, the neurotransmitter systems relevant there recover as the receptors gradually become more sensitive again.
Unfortunately, there is no evidence that deprivation of stress could lead to the regeneration of stress regulatory systems damaged in ADHD. This is also not very likely, since ADHD is usually not a consequence of chronic stress, but an effect of certain gene variants that reduce dopamine and noradrenaline levels in the same way that chronic stress does
ADHD could also be described in external terms as extreme hypersensitivity of the stress systems. Nevertheless, even very extensive stress withdrawal is unlikely to be done in such a way that adequate participation in life remains possible. Preventing a person from ever having stress again is nearly impossible - and in some ways nonsensical. After all, stress is fundamentally a very healthy reaction (see: stress benefits).
Furthermore, ADHD genes and additional chronic stress together can cause an intensification of the symptoms. A subclinical ADHD, which reaches the severity of an ADHD disorder due to additional chronic stress, would be conceivable. This picture is consistent with reports that the successful treatment of comorbid rhinitis in ADHD patients significantly improved ADHD symptoms, or that the elimination of food intolerance through diet had the same effect. This may also be a key to understanding late onset ADHD.
In any case, for ADHD sufferers, developing an awareness that chronic stress is their worst enemy should certainly be therapeutically helpful. Acute stress, on the other hand - well dosed - can be quite helpful.
According to this mechanism, excessive and prolonged release of cytokines may contribute to reduced sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids.7 Cytokine pathways such as p38 MAPK also cause an interruption of glucocorticoid-receptor communication.89
22.214.171.124.1. Downregulation during stress: desensitized cortisol receptors prevent stress system deactivation = 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 to work at 100% will eventually be damaged if it is constantly working at 130%.
However, since the (gluco-)corticoid receptors are less sensitive after prolonged stress due to downregulation, they do not perceive this signal. The shutdown of the stress systems fails to occur.10 As a result, CRH levels remain permanently elevated and permanently trigger CRH-mediated symptoms. This mechanism has already been outlined 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, whereas the ADHD-I subtype very often shows an exaggerated 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 may hold the central key to the future treatment of ADHD.
126.96.36.199.2. Downregulation during chronic stress: glutamate receptors in the mPFC
Chronic unpredictable stress leads to deregulation of glutamate balance in mice, resulting in downregulation of glutamate receptors in the mPFC.12 This also correlates with task switching problems.
Downregulation of glutamate receptors indicates excessive glutamate levels. This is consistent with the fact that chronic stress reduces GABA levels. GABA inhibits glutamate.
188.8.131.52.3. Downregulation in chronic stress: dopamine D2 receptors in the mesolimbic system
Chronic unpredictable mild stress caused anhedonia, a typical depression symptom triggered by chronic mild stress, in 70% of rats in several studies. 30% of the rats were found to be stress resistant.1314
In one study, stress-resistant rats showed downregulation of D2 receptors throughout the brain after 2 weeks, with the exception of the medial VTA (decrease in receptor protein). This appeared to be an internalization of the receptors, because receptor mRNA (expression) remained unchanged
In the stress-responsive rats, this downregulation was evident after 5 weeks. Whereas the stress-responsive rats showed no change in receptor mRNA expression, it increased in the stress-resilient rats after 5 weeks, such that the increase in expression after 5 weeks had balanced the number of D2 receptors. Thus, the stress-resilient rats showed strong neurobiological plasticity of dopamine D2 receptor density and mRNA expression, in contrast to the stress-sensitive animals.14
Another study found no association between stress-related anhedonia and differences13
- in the ventral striatum to
- D1 expression
- D2 expression
- NMDA NR2B receptor
- in the dentate gyrus to
- BDNF Expression
- in the paraventricular nucleus of the hypothalamus
- Arginine / Vasopressin
Differences were found in anhedonia
- in CA3 of the ventral hippocampus:
- Upregulation of BDNF mRNA in the stress-resilient group
- Downregulation of vascular endothelial growth factor (VEGF) mRNA in the stress-sensitive group
Further, 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 is the same adaptation mechanism at work that attempts to compensate for long-term fluctuations in neurotransmitter or hormone levels. Whereas downregulation is an adaptation to excessively high neurotransmitter/hormone levels, upregulation is the result of excessively low neurotransmitter/hormone levels. Receptor systems respond to long-term levels that are too low 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 emergence of increased excitation of neurons as a pathological permanent 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) while at the same time a membrane depolarization occurs, this leads to an above-average calcium current. Such excessive calcium currents cause phosphorylation processes to become independent of calcium. This is the basic mechanism for enhancing synaptic transmission and is likely to be 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 of the stress systems.
During stress, the stress hormone CRH is released in the hypothalamus. This has an excitatory effect on hippocampal cells by reducing calcium-dependent potassium conductance.
184.108.40.206. Norepinephrine release decoupled from external stimuli
Increased doses of CRH over time cause the excitatory effect to manifest itself permanently. This means that an increased cellular excitation level is maintained regardless of the presence of CRH.18
The phasic activity of cells of the locus coeruleus serving attention is a reaction to incoming signal stimuli from outside. 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 spacing).
A higher amount of CRH initially increases excitability and thus norepinephrine release. However, a permanently increased amount of CRH decouples norepinephrine release from the phasic stimulus in the long run. Norepinephrine is then released independently of incoming stimuli. This leads to a deterioration of the signal-to-noise ratio, which can disrupt cognitive functions.19
In addition, stress-induced norepinephrine release increases with the frequency of a stressful experience. In the case of repeated stressful experiences, the amount of noradrenaline released due to stress is higher than in the case of the first stressful experience.20
220.127.116.11. CRH receptor downregulation reduces stress system inhibition and leads to nonspecific excitability
A permanently excessive release of CRH and/or corticosteroids (cortisol) simultaneously leads to a regression of the corresponding receptors (downregulation). Thus, in addition to the permanently increased excitatory effect of CRH, there is at the same time a reduced inhibition due to the regression of the corticosteroid receptors. This also leads to an increased non-specific psychophysiological excitability.21
The mechanism of downregulation is also likely to cause downregulation of norepinephrine receptors (adrenoceptors) due to the permanently elevated norepinephrine levels.
2.1.3. Neurotoxic effects of stress hormones in chronic stress
18.104.22.168. Glucocorticoids (cortisol)
See ⇒ Neurotoxic effects of glucocorticoids (cortisol) in prolonged stress In the article ⇒ Cortisol in the section ⇒ Hormones in ADHD in the section ⇒ Neurological aspects.
2.1.4. Altered gene expressions 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 prolonged stress leads to different gene expressions again.
- During stress, the catecholamine neurotransmitter systems are primarily affected. The TYH gene regulates tyrosine hydroxylase, which is produced in the adrenal glands and brain. Tyrosine hydroxylase (TYH) is the enzyme that catalyzes the conversion of the amino acid L-tyrosine to the amino acid levodopa, from which adrenaline, dopamine, and noradrenaline are produced. This is thus the rate-determining reaction step in the biosynthesis of the catecholamines.22
- Prolonged stress causes chronic demethylation of the CRH gene in adult mice.23
- Depending on the duration, stress causes different transcription factors of the TYH gene to be addressed
- Short-term stress (3 min) causes phosphorylation of CREB-1 and Jun
- Medium stress (30 - 120 min) causes de novo synthesis of transcription factors such as c-fos and EGR1
- Prolonged stress activates EGR1 and FRA224
Depending on the duration of stress, the TYH gene is thus expressed differently. This manifests itself in different gene activity, which alters epinephrine, dopamine and norepinephrine availability.
2.1.5. Atrophy in different brain areas
Chronic unpredictable stress causes atrophy (tissue shrinkage) in quite a few brain areas in rats:25
- Different cortical areas
- Prelimbic cortex
- Cingulate cortex
- Insular cortex
- Retrosplenial cortex
- Somatosensory cortex
- Motor cortex
- Auditory cortex
- Perirhinalentorhinal cortex
- Dorsomedial striatum
- Nucleus accumbens
- Bed nucleus of the stria terminalis
- Multiple brainstem nuclei.
At the same time, functional connectivity increases within a network consisting of these regions.
Groups of high-stress responders and low-stress responders emerged.25
- 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 to the fight-or-flight system.
- High-stress responders and low-stress responders were further distinguished based on functional connectivity in a network between the brainstem and limbic system. These are believed to represent the first known potential imaging predictive biomarkers of an individual’s resilience vulnerability to stressful conditions.
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 comprehensively presented 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 reward circuitry, stress-induced neuroplasticity, and sensitization to psychostimulants.26 Immediately after singular stress, ΔFosB is barely detectable, but due to its longevity, it accumulates significantly 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.2728 Increased ΔFosB in reward circuits enhances sensitivity to psychostimulants such as cocaine.29 ΔFosB regulates the expression of many neuroplasticity-related genes in reward circuits after chronic drug exposure.30
2.2.3. Damage to the amygdala (increased anxiety)
22.214.171.124. Enlargement of the amygdala by serine protease “tissue-plasminogen factor”
During continuous 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.31
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.32
126.96.36.199. Amygdala neurons become hyperexcitable
Chronic stress causes the main output neurons of the basolateral amygdala to become hyperexcitable.33
More on this above at ⇒ Non-specific permanently increased excitability of nerve cells (basic principle).
2.2.4. Damage to the hippocampus (learning and memory disorders)
Chronic stress affects the hippocampus.34 The hippocampus - like the amygdala - is involved in the control of the HPA axis and thus in the regulation of CRH output.35 Therefore, damage to the hippocampus worsens the controllability of the HPA axis.363738 The hippocampus has a primarily inhibitory effect on the HPA axis.
The hippocampus is one of the most sensitive and malleable regions of the brain and very important for learning and memory processes. Within the hippocampus, signals are routed from the entorhinal cortex to the dentate gyrus through connections between the dentate gyrus and CA3 pyramidal neurons. A single neuron addresses an average of 12 CA3 neurons, with each CA3 neuron addressing an average of 50 other CA3 neurons as well as 25 inhibitory cells via axon collaterals. This results in a 600-fold gain of excitation as well as a 300-fold gain of inhibition.39 The high signal amplification makes the hippocampus particularly vulnerable.32
A moderate increase in cortisol supports memory formation through increased excitation of the hippocampus. A strong increase in cortisol (as caused by stress-induced activity of the HPA axis) disrupts these functions of the hippocampus.404142
Gonadal, thyroid, and adrenal hormones modulate changes in synapse formation and in the dendritic structure of the hippocampus, which affects the volume of the dentate gyrus (part of the hippocampus) in childhood and adulthood.39
188.8.131.52. Early prolonged stress experiences cause reduced hippocampus size in adults
184.108.40.206. Cell layer irregularities
Chronic cortisol administration caused cell layer irregularities in the hippocampus in primates.54
220.127.116.11. Soma shrinkage and condensation
Chronic cortisol administration caused shrinkage and condensation (compaction) of the cytosoma (cell body) in the hippocampus of primates.54
2.24.4. Core pyknosis
Cortisol causes nuclear pyknosis (condensation of chromatin in the nucleus and simultaneous shrinkage of the nuclear membrane) in primates in the hippocampus.54
18.104.22.168. Prolonged stress reduces apical dendritic trees in the hippocampus
Prolonged massive stress causes a reduction of the apical (apical: facing the cortex) dendrite tree (dendrites: cell processes of neurons) of pyramidal cells in the CA1 and CA3 regions of the hippocampus. As a result, the apical dendritic tree has fewer branches and a shorter total length.5539 This effect is mediated by cortisol.5443
If hippocampal neurons are impaired in activity due to reduced dendrites, this reduces the hippocampus’ ability to control stress.
This can lead to a vicious cycle in which increasingly poorly controlled stress leads to greater and longer cortisol release, which further and further impairs the hippocampus and reduces its stress control.32
22.214.171.124. Prolonged 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 change of the brain,
- Participate in contact mediation between presynapse and postsynapse
and which furthermore
- Signal molecules are.
Persistent stress decreases transcription of the cell adhesion molecule NCAM-140, causing a reduction in the size of the hippocampus.32
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 that include those mentioned, accompanied by deficits in declarative episodic, spatial, and contextual memory. From a therapeutic perspective, it is important to distinguish between permanent cell loss and reversible atrophy.46
126.96.36.199. Cortisol enhances glutamate action at NMDA receptors in the hippocampus
Cortisol enhances the action of the excitatory neurotransmitter glutamate at NMDA receptors. This firstly increases the calcium influx into hippocampal neurons and secondly influences the hippocampal serotonin system towards increased excitation.55
This mechanism basically improves learning. However, if the cortisol load is too strong or too long, the hippocampus is damaged by it.32
188.8.131.52. Norepinephrine increased
Chronic stress caused by movement restriction induced in the hippocampus of rats:56
- Norepinephrine increased by 104
- Norepinephrine transporterreduced 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:57
Locus coeruleus: alteration of noradrenergic cells
- on the first day increase by 33 % (acute stress)
- in the 2nd week increase by 8 % (from now on chronic stress)
- in the 4th week loss by 6%.
- in the 8th week loss by 24 %.
- in the 16th week loss by 30%.
As a result, norepinephrine 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 run.58 Since the PFC is involved in inhibiting the HPA axis (stress axis), prolonged high cortisol levels lead to impaired inhibition of the HPA axis.5960 This is also a vicious cycle.
184.108.40.206. Continuous stress reduces apical dendritic trees in the PFC
Prolonged stress causes a reduction in the size of neurons and dendrites in the PFC by inducing marked and sustained ERK1 / 2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction in phospho-CREB expression in various cortical and subcortical regions.61
220.127.116.11. Cortisol reorganizes dendritic trees in PFC and hippocampus
The changes in dendritic trees in the PFC caused by prolonged high cortisol levels are similar to changes in the hippocampus.62
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 pathway VTA / nucleus accumbens63
- Reduced BDNF level in the hippocampus64
In rats, episodic psychosocial stress (4 times in 10 days) caused an increase in BDNF in the VTA, whereas chronic 5-week psychosocial stress caused a blunted BDNF response.65
2.2.7. Changes in the serotonergic system due to chronic stress
Repeated chronic stress induces changes in serotonin release in dorsal raphe nuclei during acute stress in mice. The resulting behavioral and functional adaptations to chronic stress appear to be mediated by regulatory changes in microRNA.66
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 points to changes in the cortisolergic system. Chronic stress is regularly accompanied by decreased basal cortisol levels67 (mild tonic hypocortisolism). The schematic processes of how the cortisolergic system breaks down can be found ⇒ Breakdown of the cortisol system over the stress phases In the article ⇒ The stress systems of humans - basics of stress in the chapter ⇒ Stress.
In ADHD, basal cortisol levels are also reduced. This affects all ADHD subtypes.
2.2.9. Changes of 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.6869
If the circadian rhythm (here: of the cortisol day level) is artificially leveled, this leads to an attenuated shutdown of the HPA axis (there at least of ACTH).7071
It is our understanding that ADHD-HI and ADHD-C are often characterized by HPA axis shutdown problems.
Cortisol is also capable of resetting peripheral oscillators in additional body tissues:70
There appears to be an important relationship between disrupted circadian rhythms and allostatic load.7273 The master circadian clock in the SCN of the hypothalamus controls all circadian rhythms in physiology and behavior.74 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 (uter including glucocorticoids). Glucocorticoids are able to “reset” some (but not all) peripheral clocks in the brain and in the body (e.g., in the liver).75
In the brain, glucocorticoid rhythms modulate the expression of clock proteins in the oval nucleus of the bed nucleus of the stria terminalis and in the central amygdala.76 In contrast, the basolateral nuclei of the amygdala and the dentate gyrus of the hippocampus express diurnal rhythms of PERIOD2 (a central Clock component) opposite to the central amygdala. Adrenalectomy (removal of the adrenal gland, in whose cortex, among other things, cortisol is synthesized) affects the rhythm of the central amygdala.77
Disrupted or absent circadian patterns may lead to unhealthy regulation of the HPA axis and thus contribute to allostatic load. Thus, both disruption of the HPA axis and disruption of circadian rhythms could have interacting effects and contribute to shifts in resilience and vulnerability.78
In-depth on stress and circadian system disorders: Wolf, Calabrese (2020).79
2.2.10. Changes in energy storage in fat due to chronic stress
Chronic stress causes34
- Storage of energy in visceral fat depots due to combination of hypercortisolism and hyperinsulinemia
- Suppression of the gonadal/growth hormone/thyroid axis.
- Central obesity
- Endothelial dysfunction
2.3. Mechanisms of action of acute stress
Acute stress causes:
- Glucocorticoid secretion increased34
Catecholamine release increases34
Dopamine release in the brain increased8081 82 83 84
- Which is probably also mediated via the stress hormone CRH85
- Reduction of dopaminergic activity in the dorsal ventral tegmentum in adults by stress86
- Increase in dopaminergic activity in the ventral part of the ventral tegmentum in adults86
- Increase in tonic87 and phasic88 dopamine in the nucleus accumbens during novel inescapable/uncontrollable stress. In chronic stress, decrease in tonic dopamine below baseline until the stressor ends. This corresponds to the individual’s primary and secondary assessment of a stressor that cannot be removed
- These changes in tonic dopamine in the nucleus accumbens are controlled by the mPFC.87
- Acute and repetitive stress activates the entire dopamine system, particularly addressing the associative (dorsal) striatum, which is important for object acuity, whereas in chronic stress-induced depression, blunting of the dopamine response occurs mainly in neurons projecting to the ventromedial striatum, where reward-related variables are processed89
- Whereas electrophysiological studies concluded that aversive stimuli inhibit the activity of most VTA dopaminergic neurons and increase dopaminergic activity only in a small subset of VTA dopaminergic neurons, microdialysis studies showed that various stressors cause a robust dopaminergic increase in extracellular dopamine and its metabolites in the nucleus accumbens and mPFC, to which the ventral tegmentum projects. In acute (first-time) stress, in the nucleus accumbens, the increase begins immediately, reaches its maximum after 30 to 40 minutes, and returns to baseline after 70 to 80 minutes. With repeated or chronic stress, the increase in the nucleus accumbens decreases to zero and further to a decrease in dopamine with a maximum within 80 to 120 minutes. In the mPFC, acute stress showed a dopamine increase during stress and a further increase at the end of the stressor. Early childhood stress (malnutrition during pregnancy) correlated with no dopamine increase and a dopamine decrease after the end of stress.90
- Possibly, there are (at least) two subgroups 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 phasically stimulated by aversive stimuli.91
- Even a single stressful experience not only uniquely increases dopamine release in the ventral tegmentum (VTA) but additionally increases the readiness of dopaminergic cells in the VTA to release dopamine during future stressful experiences. Thus, acute stress may alter the responsiveness of VTA dopamine neurons to future stressors or rewards.90 This increase in dopaminergic responsiveness to subsequent stressful experiences does not occur when glucocorticoid receptors are previously blocked.92939495 The increase in dopaminergic responsiveness to cocaine administration did not occur when the dopamine D1 receptor was blocked in the process.93
- Dopamine release in the brain increased8081 82 83 84
- Inhibition of the hypothalamic-pituitary axis and thus of reproduction97
- Insulin resistance in the liver34
- Insulin resistance in skeletal muscle34
A single 8-hour immobility stress changed the morphology of microglial cells toward more intense and larger cell bodies in substantia nigra and locus coeruleus. This microglial response persisted during 16 weeks of chronic stress. Inflammation levels could be detected by increased iNOS protein expression.
Intermittent acute tail shock stress increased extracellular dopamine by 25% in the striatum, 39% in the nucleus accumbens, and 95% in the medial frontal cortex in rats compared with baseline.83 Overstimulation of the dopamine D1 receptor in the PFC impairs working memory.98 The PFC requires balanced dopamine levels for optimal function.9899
2.4. Different consequences of acute and chronic stress
2.4.1. Consequences of acute stress
Acute stress can trigger:100
- Allergic phenomena, such as
- Angiokinetic phenomena, such as
- hypertensive or hypotensive seizures
- Pain, like
- Abdominal pain
- Pelvic pain
- Low back pain
- gastrointestinal symptoms such as
- Digestive disorders
- Panic attacks
- psychotic episodes
2.4.2. Consequences of chronic stress
Chronic stress can trigger:100
- Physical manifestations
- Cardiovascular cardiovascular phenomena, such as
- Atherosclerotic cardiovascular diseases
- Neurovascular degenerative diseases
- Osteopenia / Osteoporosis
- Metabolic disorders, such as
- Metabolic syndrome
- Type 2 diabetes mellitus
- Cardiovascular cardiovascular phenomena, such as
- Behavioral and or neuropsychiatric manifestations
- Executive and/or cognitive dysfunction
- Sleep disorders like
- Excessive daytime sleepiness
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. ↥
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. ↥ ↥
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 ↥
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 ↥ ↥
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. ↥
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. ↥
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. ↥ ↥
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. ↥ ↥
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 ↥
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 ↥
Aldenhoff (1990): Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen, in: Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 183 ↥
Aldenhoff, Erregungsungleichgewicht als mögliche Ursache seelischer Erkrankungen (1990) in Beckmann, Osterheider: Neurotransmitter und psychische Erkrankungen, Springer, Seite 183 ↥
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 ↥
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 ↥
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. ↥ ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
Trapp, Holzboer (2013): Molekulare Mechanismen der Glucocorticoidtherapie; in: Ganten, Ruckpaul (2013): Erkrankungen des Zentralnervensystems, Springer, Seite 104 ↥
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 ↥
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. ↥
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. ↥
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 ↥
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 ↥
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 ↥ ↥
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. ↥
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. ↥
Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 45 ↥
Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 44 ↥
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 ↥
Wellman (2001), zitiert nach Steckler, Kalin, Reul (2005): Handbook of Stress and the Brain, Teil 1; Elsevier, Seite 809 ↥
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. ↥
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 ↥
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. ↥
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. ↥
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 ↥ ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
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. ↥
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 ↥ ↥
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 ↥
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. ↥
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. ↥ ↥
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 ↥
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. ↥
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 ↥ ↥
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. ↥
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. ↥
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. ↥ ↥
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. ↥
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. ↥
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 ↥ ↥
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 ↥