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10. Dopamine and stress

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10. Dopamine and stress

There is a close connection between the dopaminergic system and the stress response in humans. If the dopaminergic system is disturbed, this also causes disturbed stress processing. Likewise, early or chronic stress causes impairment of the dopaminergic system.

10.1. Dopamine system influences stress systems

The dopamine transporter (DAT) regulates the HPA axis (stress axis) centrally and peripherally.1

DAT-/- rats (these have almost no functional DAT) show1

  • During acute immobilization stress, abnormal autonomic respiratory and cardiovascular responses and a delayed increase in body temperature
  • After acute movement restriction stress a profound dysregulation of the pituitary gland with simultaneously increased peripheral corticosterone

DAT+/- rats (these have reduced DAT function) show1

  • Reduced body temperature during acute immobilization stress
  • After acute exercise restriction stress, a similarly active pituitary as control animals with normal DAT, with concomitantly higher peripheral corticosterone than DAT-/- rats
  • Increased vulnerability to stress in female rats with alterations reminiscent of PTSD

Decreased DAT could mediate increased vulnerability to stress through decreased maternal caregiving behavior.2

Up-regulation of DRD1, DRD2, DRD3, DRD4, DBH, DAT, and BDNF and down-regulation of serotonin transporter, MAO-A, and COMT correlate with stress resilience in humans modulated by dopaminergic and serotonergic pathways.3 Another study also found increased D2 sensitivity in rats that responded resiliently to traumatizing stress.4

Dopamine deficiency in the PFC leads to an increased response of mesolimbic dopaminergic neurons to stress.5 One symptom of ADHD is an impaired ability to regulate stress.

10.2. Stress influences dopamine system

Depending on the type of stressor and the duration of stress exposure, different changes in the dopamine system result

Whereas acute (one-time) stress has a dopamine-increasing effect, chronic unpredictable mild stress (CUMS) (only) leads to reduced VTA dopaminergic activity after a duration of exposure of more than 4 weeks. In contrast, VTA dopamine activity remains elevated after prolonged chronic social defense stress (CSDS).
It is open to what extent different areas of the VTA might produce different dopaminergic activities. Stimulation of VTA neurons with different excitability could lead to conflicting results despite the apparent depressive behavioral phenotype
Further, the VTA-NAc dopamine system is activated in response to reward stimuli. How DAergic neurons link rewarding and aversive stressful stimuli may be critical for understanding stress-induced modulation of the VTA-NAc dopaminergic reward system and its effects on stress-related adaptive behavior in response to reward demands.6

10.2.1. Dopamine and acute stress

Single 30-min immobilization stress increased firing rate and burst firing of VTA dopamine neurons in rats.7
Pain stress (foot shocks) such as 2 hours of immobilization stress cause an increase in the population activity of dopaminergic VTA neurons (an increased number of spontaneously firing dopamine neurons) with a significant increase in the average percentage of burst firing, but without affecting the average firing rate. This response could be suppressed by administration of tetrodotoxin to the ventral hippocampus, suggesting that the ventral hippocampus is involved in mediating the dopaminergic response and the behavioral stress response mediately affecting the HPA axis.8910

fifteen minutes of immobilization or tail pinching increased extracellular dopamine levels in nucleus accumbens and dorsal striatum (measured by high-speed chronoamperometry).11

A study in mice using the tail suspension test (TST) found that mice with the D1 receptor deactivated showed significant depression symptoms, whereas mice with the D2 receptor deactivated did not. Dopaminergic D1 signaling in the nucleus accumbens appears to play a central role in modulating stress coping behavior in animals under tail suspension.12

10.2.2. Alteration of the dopaminergic system by early stress

Prenatal daily mild stress induces increased striatal dopamine transporter binding in adult nonhuman primates.13

Mitochondrial impairments and metabolic stress cause striatal dopamine efflux by means of the DAT. Disturbances of dopamine homeostasis resulting from energetic impairments seem to contribute to the pathogenesis of neurodegenerative diseases.14

Social stress in adolescence may trigger dopamine deficiency in mPFC in adulthood through upregulation of DAT.15

Birth complications may influence the way in which DAT is altered by stress in adult rats.16 This is very close to the ADHD BIld.

Whether early prolonged stress always reduces dopamine levels in the striatum is an open question. Also, with regard to psychoses associated with increased dopamine levels in the striatum, it has been reported that these often correlated with early prolonged stress experiences.17
Possibly, this could depend on the existing gene disposition, the timing of stress exposure, or the type of stressor.

In early trauma, neurological change in the brain occurs in other brain regions depending on the type of trauma, and (arguably not only, but also) in the very regions responsible for processing those skills that were mistreated.

  • Early sexual abuse causes thinner cortex in regions representing the genital area.18
  • Early emotional maltreatment causes a reduced volume of brain areas responsible for self-reflection, self-recognition, and emotional regulation.19
    • This explains conclusively for us why, for example, borderline patients have particular difficulties with self-reflection and, for example, find it very difficult to comprehend that their inner tensions result from contradictory simultaneously existing schemas20. These difficulties in resolving these inner contradictions lead to typical black-and-white thinking, in which gray shades in between or both/and cannot be tolerated.

10.2.3. Epigenetic inheritance of stress experience

Chronic unpredictable maternal stress prior to conception resulted in disruption of the mPFC dopamine system and offspring stress responses in rats. The offspring showed:21

  • Elevated serum corticosterone levels
  • Elevated CRH levels
  • Reduced ratio of dihydroxy-phenyl acetic acid (DOPAC) to dopamine in mPFC
    • In the right mPFC even lower than in the left one
    • In the right mPFC lower in females than in males
  • Reduced DAT in the mPFC
  • Decreased noradrenaline transporters in the mPFC
    • In the right mPFC even lower than in the left one
    • In the right as well as in the left mPFC lower in females than in males
  • Reduced COMT level
    • In the left mPFC of female progeny (unchanged in males)
    • In the right mPFC of both female and male progeny
    • In the right mPFC even lower than in the left one
    • In the right as well as in the left mPFC lower in females than in males

10.2.4. Alteration of the dopaminergic system by chronic stress

The mesoprefrontal dopaminergic system is particularly vulnerable to chronic stress.

Chronic stress leads to downregulation of the mesolimbic dopamine system.2223

  • Blunting of the dopaminergic response to acute stress.242526
  • Drop in tonic dopamine in the nucleus accumbens below baseline levels prior to initial occurrence of the stressor until the stressor ends. This corresponds to the individual’s primary and secondary appraisal of an unmanageable stressor.27
  • Acute and repetitive stress activate 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 processed24

Chronic stress appears to produce different effects depending on the stressor:

  • Chronic noise stress caused dopamine decreases in the PFC and worsened performance in delayed responses but not performance in undelayed responses.28
  • Chronic cold stress sensitized dopaminergic and noradrenergic neurons in the PFC, but probably not dopaminergic subcortical neurons.29 Chronic mild cold stress reduces the dopaminergic response to acute stress but does not appear to directly affect the perception of reward.30
  • Chronic psychosocial stress caused, among other things, a delay in the activation of working memory.31
  • Chronic stress appears to cause impairment of working memory via a hypodopaminergic mechanism in the PFC.32
10.2.4.1 Dopamine changes due to chronic immobilization stress
10.2.4.1.1. Still no dopamine reduction within 10 days

Acute (one-time) or short-lasting (here: 10 days) immobilization stress In contrast, does not (yet) cause a reduction in dopamine release.

In the striatum of rats, single immobilization stress (compared with controls) induced33
* Increased enkephalin gene expression (enkephalin is an endogenous opioid)
* Increased DAT binding
* 3-fold increased corticosterone levels compared to paired controls

After each 10-min immobilization stress for 10 consecutive days, no change in dopamine levels (compared with the response on day 1) was found in the PFC, dorsal striatum, or nucleus accumbens in DBA/2 or C57BL/6 mice by high-performance liquid chromatography (HPLC)

immobilization stress for 10 minutes per day caused increased levels of 3-4-dihydroxyphenylacetic acid, homovanillic acid, and 3-methoxytyramine in the nucleus accumbens (mesolimbic dopamine system) and 3-4-dihydroxyphenylacetic acid in the PFC (mesocortical dopamine system) in mice on the first day
By day 5, the changes in 3-methoxytyramine and homovanillic acid concentrations in the nucleus accumbens disappeared
On day 10, there was no longer an increase in 3-4-dihydroxyphenylacetic acid concentration
The increase in 3-4-dihydroxyphenylacetic acid level (mesocortical dopamine system) persisted on day 5 and on day 10
Also, on day 10, 10 minutes of immobilization stress was sufficient to increase 3-4-dihydroxyphenylacetic acid levels in the PFC frontal cortex of mice that had suffered 2 hours of immobilization stress for 9 days each.34

Another study found by in vivo microdialysis after repeated immobilization stress of 1 hour/day for 6 days on the first day an increased dopamine release on fixation as on release thereafter. While the dopamine increase on immobilization decreased to normalized in the following days, the dopamine increase on release remained unchanged.35
Repeated, once-daily stress by 15 minutes of immobilization or tail pinching increased extracellular dopamine levels in nucleus accumbens and striatum (measured by high-speed chronoamperometry) the first time. The effect of restraint on mesolimbic and, to some extent, nigrostriatal dopamine neurotransmission increased progressively with each daily exposure. While the increase in extracellular dopamine elicited by tail pinching varied across experimental days, no reliable daily enhancement of electrochemical responses to this stress was observed in any of the regions studied.11

2 hours of immobilization stress over 10 days caused an increase in the population activity of dopaminergic VTA neurons (an increased number of spontaneously firing dopamine neurons) with a significant increase in the average percentage of burst firing, but without affecting the average firing rate.8 The increased activity of the dopamine neuron population appears to:6

  • modulate the tonic extrasynaptic dopamine level
  • puts the VTA neurons in a “response state” to phasic events.

Only neurons that are in a tonic firing state can be phasically activated by the relevant salient stimulus (either threatening or rewarding).6

12 days of immobilization stress (1 hour/day) decreased D1 receptor density in the nucleus accumbens. D2 receptor density remained unchanged.36 After 10 days of immobilization stress (2 hours/day), an increase in D2 receptor binding was found in the nucleus accumbens shell.33

10.2.4.1.2. Dopamine reduction after a few weeks

Chronic immobilization stress or chronic social stress causes blunting of the mesolimbic dopaminergic system (which influences motivation) in animals that do not habituate to the stressor, possibly due in part to sustained CORT elevations.

Repeated immobilization stress followed by isolation (compared to single stress)33
* Decreased enkephalin gene expression
* Reduced DAT binding
* Increased D2 binding in the nucleus accumbens
* Increased corticosterone levels compared to single stress and controls kept in isolation
* No habituation effect seems to occur here
Repeated immobilization stress without subsequent isolation (compared to single stress)33
* Unchanged increased enkephalin gene expression
* Increased DAT binding
* Increased D2 binding in the dorsal striatum
* Unchanged corticosterone levels compared to single stress and non-isolated controls
* This seems to reflect a habituation effect

  • Chronic social stress, for weeks after it has ended37
    • Decreased enkephalin gene expression
    • Reduced DAT binding
    • Increased dopamine D2 receptor binding

This suggests dopamine receptor upregulation as a result of dopamine deficiency.

Rats were restrained for prolonged periods of 8 hours a day, 5 days a week. The chronic severe stress induced by this resulted in a loss of dopaminergic cells in:38

  • Hypothalamus (here: nucleus arcuatus): Loss of dopaminergic cells
    • in the 2nd week by 11
    • in the 4th week by 38
    • by 56% in the 8th week.
    • by 57 % in the 16th week.
  • VTA: loss of dopaminergic cells
    • in the 2nd week by 10
    • in the 4th week by 19
    • by 40% in the 8th week.
    • by 41% in the 16th week.

Chronic immobilization stress further resulted in loss of dopaminergic cells in the substantia nigra;39

  • Substantia nigra: loss of dopaminergic cells
    • in the 2nd week by 18
    • in the 4th week by 30
    • by 40% in the 8th week.
    • by 60% in the 16th week.

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.

After each 2-h immobilization stress for 10 consecutive days, no change in dopamine levels was found in the PFC, dorsal striatum, or nucleus accumbens in DBA/2 or C57BL/6 mice by high-performance liquid chromatography (HPLC).40.

Acute immobilization stress markedly increased c-Fos and FosB and weakly increased DeltaFosB in the PFC and nucleus accumbens
10 days of immobilization stress abolished the induction of c-Fos, decreased the induction of FosB, and greatly increased deltaFosB levels. DeltaFosB was particularly increased in the PFC, nucleus accumbens, and basolateral amygdala, with lower increases in other regions.41

7 to 8 days of immobilization stress (3 to 4 hours/day) decreased the strength of excitatory synapses at D1-MSNs but not at D2-MSNs of the nucleus accumbens nucleus.42 This may suggest that a D1-MSN-specific change in excitatory transmission is responsible for the induction of anhedonia.6

10.2.4.2. Dopamine changes due to inescapable pain stress

Rats that received inescapable electric shocks for 3 weeks showed reduced dopamine release in the nucleus accumbens for weeks after the last stressor.43 In the mPFC, dopamine and serotonin levels that were still decreased 3 days after the last stress were restored (serotonin) or increased (dopamine) after 14 days.

10.2.4.3. Dopamine changes due to chronic psychosocial stress

Chronic stress reduces striatal dopaminergic activity over the long term. Institutional neglect, early childhood stress, or maltreatment inhibit striatal reward function, which is dopaminergically mediated.44454647 Long-term exposure to psychosocial stress correlates with downregulation of:24

  • Dopamine
    • Especially in the striatum
  • Autonomic and endocrine systems

One study found that in subjects with low long-term psychosocial stress exposure, dopamine synthesis increased during acute stress, whereas in subjects with long-term exposure to psychosocial adversity (in terms of a summation of lifetime psychosocial stress experiences), the dopaminergic stress response in the striatum was reduced. The lower dopaminergic stress response in the striatum also correlated with an increased subjective response to acute psychosocial stress.24

In rats, 4 times of psychosocial stress within 10 days caused sensitization of the dopamine stress response, whereas chronic 5 weeks of psychosocial stress caused a flattening of the dopamine stress response in the nucleus accumbens.48

Social isolation after single social stress causes decreased DAT binding in the striatum.49 Chronic social stress reduces the number of DAT in the striatum.50
Social stress decreased the density of DAT in the dorsolateral putamen of the striatum, and repeated social stress in the nucleus accumbens of the striatum, respectively, of socially inferior rats when they showed a flattened corticosterone response to acute stress. Socially inferior rats without a flattened corticosterone stress response did not show this.
Dopamine D2 receptor density was increased in the striatum nucleus accumbens after single social stress and in the putamen and nucleus accumbens after repeated social stress, in all socially subordinate rats (i.e., independent of the corticosterone stress response).
No group showed altered D1 receptors.51

Chronic social stress leads to decreased52 in female cynomolgus monkeys, unchanged53 dopamine D2 receptors in male cynomolgus monkeys, and increased cocaine addiction susceptibility.

10.2.4.4 Dopamine changes due to chronic unpredictable mild stress (CUMS)

Chronic unpredictable mild stress (CUMS) causes downregulation of dopaminergic mesolimbic pathways with a reduction in dopamine levels in the nucleus accumbens, resulting in decreased sensitivity to rewards and anhedonic behaviors.23
* This is consistent with the changes in decreased dopamine levels and desensitized reward expectancy known to occur in ADHD. Neurophysiological correlates of reward in ADHD In contrast, acute stress increases dopamine levels (also) in the nucleus accumbens during reward expectancy in healthy individuals.54

Results on dopamine changes by CUMS in the nucleus accumbens are inconsistent

CUMS exposure caused a reduction in dopamine release in the nucleus accumbens shell after 24 hours, which diminished somewhat after 14 days but was still very strong compared with controls, as was the anhedonic escape deficit. in the mPFC was found by microdialysis:55

  • a short-term reduction in basal dopamine levels, which returned to control levels on day 14
  • a decrease in dopamine accumulation on day 3, followed by a significant increase above control levels on day 14
  • a significant decrease in extraneuronal serotonin basal levels on day 3, but not on day 14

A 7-day CUMS exposure decreased basal as well as accumulated extracellular dopamine and serotonin levels in the nucleus accumbens shell and mPFC (microdialysis).55

Chronic unpredictable mild stress (CUMS) showed no effect on dopamine levels in the nucleus accumbens or PFC (microdialysis) over a period of 14 days or 30 days, but resulted in weight loss in different rat strains.5657
5 weeks of CUMS caused anhedonia and increased DA levels in the nucleus accumbens but not in the dorsal striatum (rapid cyclic voltammetry/HPLC).58 7 weeks of CUMS increased DA and its metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-methoxytyramine (3-MT) by 47% to 77% in the limbic forebrain but not in the dorsal striatum. Serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were also increased in the limbic forebrain.59

7 to 9 weeks of chronic unpredictable mild stress, such as that used as a depression model in animals, was treatable with the dopamine D2 agonist pramipexole (SND-919).60
8 weeks of CUMS caused a decrease in D2 receptor binding in the limbic forebrain but not in the striatum. 5 weeks of imipramine abolished this completely. In nonstressed animals, imipramine decreased D1 receptor binding in the limbic forebrain and striatum. However, in stressed animals, imipramine did not significantly alter D1 receptor binding in either region. Stress slightly increased D1 receptor binding in the striatum. All changes in receptor binding resulted from changes in receptor number, rather than changes in receptor affinity.61

16 days CUMS62

  • increased D1 receptor density in the limbic system by 29
  • increased 5HT-2A receptor density in the PFC by 52%.

Chronic food restriction resulting in weight loss of 20% to 30% (although this is more likely to be an intense stressor) reduced basal extracellular dopamine levels by up to 50% in the nucleus accumbens but not in the dorsal striatum (in vivo microdialysis).63

An optogenetic inhibition of VTA dopamine neurons64

  • depressive behaviors induced without CUMS
  • after 8 to 12 weeks of CUMS, depressive behavior lifted

8 to 12 weeks of CUMS decreased the normal burst activity of VTA dopamine neurons without altering the mean firing rate64 and the percentage of spikes in bursts65. There was a significant decrease in the activity of the VTA dopamine neuron population, which represents a recruitable pool of DA neurons for burst firing. Such a decrease in the number of spontaneously firing dopaminergic neurons affects the dopamine response to external stimuli.65

HCN channels (these mediate depolarizing cation influx, Ih) appear to affect the excitability of VTA dopamine neurons. The population activity, frequency of tonic firing, and frequency of burst firing of VTA dopamine neurons decrease when Ih is reduced in CUMS-exposed mice. In conjunction with the decrease in Ih, knockdown of the HCN2 gene in the VTA (via RNA interference) leads to depressive and anxiety-like behavior, whereas overexpression of HCN2 in the VTA prevented CUMS-induced depressive behavior.66
Accordingly, the excitability of VTA dopamine neurons is crucial for the regulation of CUMS-induced depressive behavior.6

CUMS and DeltaFosB (ΔFosB)

Acute EMS markedly increased c-Fos and FosB and DeltaFosB (ΔFosB) weakly in the PFC and nucleus accumbens
10 days of CUMS abolished the induction of c-Fos, decreased the induction of FosB, and greatly increased the levels of DeltaFosB.41 DeltaFosB /ΔfosB) is a transcription factor of the Fos family. The stress-induced increase occurred in both dynorphin-positive (D1-MSNs) and enkephalin-positive (D2-MSNs) neurons in the nucleus accumbens.
CSDS caused increased DeltaFosB expression in the nucleus accumbens, which is even higher in resilient mice than in susceptible mice.67
CSDS increased induction of DeltaFosB:68

  • in depression-prone mice
    • in D2-MSN
      • in the nucleus accumbens nucleus
      • in the nucleus accumbens shell
      • in the dorsal striatum
  • in resilient mice
    • in D1-MSN
      • throughout the striatum
10.2.4.5. Chronic stress impairs working memory through dopamine deficiency via D1 receptor

Whereas acute stress impaired executive functions residing in the dlPFC via increased dopamine levels,69 chronic stress induced decreased dopamine levels in the PFC, which impaired working memory function in the dlPFC and thus executive functions. In this regard, chronic stress induced a marked reduction in dopamine transmission and an increase in dopamine D1 receptor density in the PFC while impairing spatial working memory. This memory impairment was ameliorated by infusions of a specific D1 receptor agonist into the PFC. Pretreatment with a D1 receptor antagonist prevented the improvement by the D1 receptor agonist. Chronic stress therefore appears to impair working memory through dopamine deficiency in the PFC via the D1 receptor.70

10.2.4.6. Chronic severe stress reduces dopamine levels

While exposure to mild stressors increased dopaminergic activity, severe chronic stressors caused decreased dopaminergic activity.71

10.2.4.7. Dopamine changes due to chronic social defense stress (CSDS)

Only some animals exposed to CSDS react with stress.
The vulnerable (depressed) group and the resilient group show different neuronal activities in the VTA after CSDS exposure
In susceptible mice, 10 days of CSDS significantly increased spontaneous firing rates and the number of burst events in VTA dopamine neurons in vivo, whereas these were unchanged in resilient animals.72
Optogenetic induction of phasic firing of VTA dopamine neurons resulted in depressive symptoms (increased social avoidance and decreased sucrose preference) at low levels of social defense stress, whereas optogenetic induction of tonic firing of VTA dopamine neurons did not.73
Moreover, VTA dopamine neurons projecting to the nucleus accumbens from susceptible mice show a significantly higher firing rate in vitro than those from controls or resilient mice. Increased dopaminergic activity of VTA-NAc neurons with a phasic firing pattern appears to be a key to susceptibility to CSDS. It is possible that resilience to CSCD could be mediated by compensatory upregulation of potassium channels in response to excessive activity.6

In Mandarin voles, 14 days induced CSDS (significantly stronger) as well as emotional stress (weaker but perceptible) compared to non-stressed animals, regardless of sex:74

  • Reduced density of dopamine D2 receptors
  • Reduced density of serotonin 1A receptors in the ACC
  • Reduced density of oxytocin receptors
  • Reduced comfort behavior (grooming)
  • Increased anxiety-like behaviors

Pretreatment with oxytocin, D2, or 5-HT1A receptor agonists in ACC decreased the reduction in comfort behavior and increased anxiety behavior in stressed mice but increased it in nonstressed mice.


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