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11. Dopamine and stress

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11. Dopamine and stress

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There is a close connection between the dopaminergic system and the human stress response. If the dopaminergic system is impaired, this also results in impaired stress processing. Similarly, early or chronic stress causes impairment of the dopaminergic system.
It is becoming increasingly clear that the dopamine system plays a key role in the response to stress, particularly in the pathological response observed in many psychiatric disorders.1

11.1. Dopamine system influences stress systems

The dopamine transporter (DAT) regulates the HPA axis (stress axis) centrally and peripherally.2

DAT-/- rats (these have almost no functional DAT) show2

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

DAT+/- rats (these have a reduced DAT function) show2

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

Reduced DAT could mediate increased vulnerability to stress through reduced maternal caregiving behavior.3

The upregulation of DRD1, DRD2, DRD3, DRD4, DBH, DAT and BDNF and the downregulation of serotonin transporters, MAO-A and COMT correlate with stress resilience in humans, which is modulated by dopaminergic and serotonergic pathways.4 Another study also found increased D2 sensitivity in rats that responded resiliently to traumatizing stress.5

Dopamine deficiency in the PFC leads to an increased reaction of mesolimbic dopaminergic nerve cells to stress.6 One symptom of ADHD is an impaired ability to regulate stress.

Moderate and severe neonatal VTA lesions alter to prevent the normal activation of dopamine, serotonin and even the noradrenergic system during stress in rats:7
As adults, these animals showed

  • in mPFC and amygdala / piriform cortex (A/PC)
    • dopamine reduced by 80 % and serotonin reduced by 70 to 75 % in the PFC
    • Metabolites were less strongly reduced, indicating increased activity of the remaining terminals
  • in the nucleus accumbens, olfactory tubercle and striatum
    • dopamine and serotonin reduced by 30-75 %
  • a flattened stress response to foot shock stress
    • stress-induced increase in dopamine in the mPFC reduced by more than 80
    • stress-induced increases in dopamine in the tubercle, accumbens and striatum and in serotonin in the striatum completely eliminated
    • stress-induced MHPG increase in A/PC blunted

11.2. Stress influences the dopamine system

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

While acute (one-off) stress has a dopamine-increasing effect, chronic unpredictable mild stress (CUMS) (only) leads to reduced dopaminergic activity of the VTA after an exposure period of more than 4 weeks. In contrast, VTA dopamine activity remains elevated even after prolonged chronic social defense stress (CSDS).
The extent to which different areas of the VTA might produce different dopaminergic activities remains open. Stimulation of VTA neurons with different excitability could lead to contradictory results despite the obvious depressive behavioral phenotype.
Furthermore, the VTA-NAc dopamine system is activated in response to rewarding stimuli. How DAergic neurons connect rewarding and aversive, stressful stimuli may be critical to understanding stress-induced modulation of the VTA-NAc dopaminergic reward system and its effects on stress-induced adaptive behavior in response to reward demands.8

11.2.1. Dopamine and acute stress

Single 30-minute immobilization stress increased the firing rate and burst firing of VTA dopamine neurons in rats.9
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 inhibited 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 by influencing the HPA axis.101112
Acute stress increases the response strength of exitatory synapses on dopamine neurons in the midbrain. The synaptic effects of stress are blocked by the glucocorticoid receptor antagonist RU486.13
15 minutes of immobilization or tail pinching increased extracellular dopamine levels in nucleus accumbens and dorsal striatum.14 Repeated restraint stress alters the response of the mesolimbic DA system to a stressor, and repeated stressors such as tail pinching facilitate the acquisition of self-administration of psychostimulants such as cocaine and amphetamine.15

A study in mice using the tail suspension test (TST) found that mice with a deactivated D1 receptor showed significant depression symptoms, whereas mice with a deactivated D2 autoreceptor did not. Dopaminergic D1 signaling in the nucleus accumbens appears to play a central role in modulating stress coping behavior in animals.16

11.2.2. Changes in the dopaminergic system due to early stress

Prenatal daily mild stress induces increased binding of the striatal dopamine transporter in adult nonhuman primates.17

Mitochondrial impairment and metabolic stress cause striatal dopamine efflux via the DAT. Disturbances in dopamine homeostasis resulting from energetic impairments appear to contribute to the pathogenesis of neurodegenerative diseases.18

Social stress in adolescence can trigger dopamine deficiency in the mPFC in adulthood through an upregulation of DAT.19

Birth complications can influence the way in which the DAT in adult rats is altered by stress.20 This comes very close to the ADHD picture.

Whether early prolonged stress always reduces dopamine levels in the striatum is an open question. It has also been reported that psychoses associated with increased dopamine levels in the striatum often correlate with early prolonged stress experiences.21
This could possibly depend on the existing gene disposition, the time of exposure to stress or the type of stressor.

In the case of early traumatization, the neurological change in the brain occurs in other brain regions, depending on the type of traumatization, and (probably not only, but also) in those regions that are responsible for processing the skills that were abused.

  • Early sexual abuse causes a thinner cortex in the regions that represent the genital area.22
  • Early emotional abuse causes a reduced volume of brain areas responsible for self-reflection, self-recognition and emotional regulation23
    • For us, this conclusively explains why, for example, borderline sufferers have particular difficulties with self-reflection and, for example, find it very difficult to understand that their inner tensions result from contradictory, simultaneously existing schemas24. These difficulties in resolving these inner contradictions lead to typical black-and-white thinking, in which gray nuances or both-and cannot be tolerated.

11.2.3. Epigenetic inheritance of stress experience

Chronic unpredictable stress of the mother before conception led to disturbances of the mPFC dopamine system and stress responses of the offspring in rats. The offspring showed:25

  • Elevated serum corticosterone levels
  • Elevated CRH levels
  • Reduced ratio of dihydroxy-phenylacetic acid (DOPAC) to dopamine in the mPFC
    • Even lower in the right mPFC than in the left
    • In the right mPFC lower in females than in males
  • Reduced DAT in the mPFC
  • Reduced noradrenaline transporters in the mPFC
    • Even lower in the right mPFC than in the left
    • Lower in the right and left mPFC in females than in males
  • Reduced COMT level
    • In the left mPFC of the female offspring (unchanged in males)
    • In the right mPFC of the female and male offspring
    • Even lower in the right mPFC than in the left
    • Lower in the right and left mPFC in females than in males

11.2.4. Changes in the dopaminergic system due to chronic stress

The mesoprefrontal dopaminergic system is particularly susceptible to chronic stress.

Neurochemical studies have shown that the DA system is activated by prolonged stress stimuli.15
Repeated restraint stress alters the response of the mesolimbic dopamine system to a stressor, and repeated stressors such as tail tweaking facilitate the acquisition of self-administration of psychostimulants such as cocaine and amphetamine.

Chronic stress leads to a downregulation of the mesolimbic dopamine system.2627

  • Acute stress activates the release of dopamine in the VTA, chronic stress reduces it2829
    • This stress-induced activation and inhibition of VTA dopamine neurons is regulated by
      • CRH
      • Opioids
      • BDNF
      • Glucocorticoids
        • Sex hormones influence this
  • Blunting of the dopaminergic response to acute stress.303132
  • Drop in tonic dopamine in the nucleus accumbens below the initial value before the stressor first occurs, until the stressor ends. This corresponds to the primary and secondary assessment of an unmanageable stressor by the individual.33
  • Acute and repetitive stress activate the entire dopamine system, which particularly addresses the associative (dorsal) striatum, which is important for object acuity, while 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 processed30

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

  • Chronic noise stress caused dopamine reductions in the PFC and worsened performance in delayed responses, but not performance in non-delayed responses.34
  • Chronic cold stress sensitized dopaminergic and noradrenergic neurons in the PFC, but not dopaminergic subcortical neurons.35 Chronic mild cold stress reduces the dopaminergic response to acute stress, but does not appear to have a direct influence on the perception of rewards.36
  • Chronic psychosocial stress caused, among other things, a delay in the activation of working memory.37
  • Chronic stress appears to cause an impairment of working memory via a hypodopaminergic mechanism in the PFC.38
11.2.4.1 Dopamine changes due to chronic immobilization stress
11.2.4.1.1. Still no dopamine reduction within 10 days

Acute (one-off) or short-lasting (here: 10 days) immobilization stress, on the other hand, does not (yet) cause a reduction in dopamine release.

In the striatum of rats, single immobilization stress caused (compared to controls)39
* Increased enkephalin gene expression (enkephalin is an endogenous opioid)
* Increased DAT binding
* 3-fold increase in corticosterone levels compared to paired controls

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

a 10-minute immobilization stress per day caused increased levels of 3-4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine in the nucleus accumbens (mesolimbic dopamine system) and of 3-4-dihydroxyphenylacetic acid in the PFC (mesocortical dopamine system) in mice on the first day.
On day 5, the changes in 3-methoxytyramine and homovanillic acid concentrations in the nucleus accumbens disappeared
On day 10, there was no further increase in the 3-4-dihydroxyphenylacetic acid concentration.
The increase in the 3-4-dihydroxyphenylacetic acid level (mesocortical dopamine system) also persisted on the 5th and 10th day.
Even on the 10th day, 10 minutes of immobilization stress was sufficient to increase 3-4-dihydroxyphenylacetic acid levels in the PFC frontal cortex of mice that had undergone 9 days of immobilization stress for 2 hours each.40

Another study using in vivo microdialysis after repeated immobilization stress of 1 hour/day over 6 days found an increased dopamine release on fixation on the first day as well as on release thereafter. While the increase in dopamine on immobilization decreased to normal in the following days, the increase in dopamine on release remained unchanged.41
Repeated, once-daily stress from 15 minutes of immobilization or tail pinching increased extracellular dopamine levels in the 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.14

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.10 The increased activity of the dopamine neuron population appears to:8

  • modulate the tonic extrasynaptic dopamine level
  • puts the VTA neurons into a “reaction 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).8

12 days of immobilization stress (1 hour/day) reduced the D1 receptor density in the nucleus accumbens. The D2 receptor density remained unchanged.42 After 10 days of immobilization stress (2 hours/day), there was an increase in D2 receptor binding in the nucleus accumbens shell.39

11.2.4.1.2. 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 persistent CORT elevations.

Repeated immobilization stress with subsequent isolation (compared to single stress)39
* Reduced enkephalin gene expression
* Reduced DAT binding
* Increased D2 binding in the nucleus accumbens
* Increased corticosterone levels compared to single stress and isolated controls
* There does not seem to be any habituation effect here
Repeated immobilization stress without subsequent isolation (compared to single stress)39
* 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, even weeks after it has ended43
    • Reduced enkephalin gene expression
    • Reduced DAT binding
    • Increased dopamine D2 receptor binding

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

Rats were restrained for 8 hours a day, 5 days a week over a long period of time. The resulting chronic severe stress led to a loss of dopaminergic cells in the brain:44

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

Chronic immobilization stress further led to a loss of dopaminergic cells in the substantia nigra;45

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

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.

No change in dopamine levels in the PFC, dorsal striatum or nucleus accumbens was found in DBA/2 or C57BL/6 mice after 2 hours of immobilization stress on 10 consecutive days using high-performance liquid chromatography (HPLC).46.

Acute immobilization stress increased c-Fos and FosB significantly and DeltaFosB weakly in the PFC and nucleus accumbens.
10 days of immobilization stress abolished the induction of c-Fos, reduced the induction of FosB and strongly increased DeltaFosB levels. DeltaFosB was particularly elevated in the PFC, nucleus accumbens and basolateral amygdala, with lower increases in other regions.47

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 core.48 This may indicate that a D1-MSN-specific change in excitatory transmission is responsible for the induction of anhedonia.8

Chronic immobilization stress, such as repeated stress from social defeat, increases both spontaneous tonic and phasic burst firing of dopamine neurons in the VTA.49

11.2.4.2. Dopamine changes due to unavoidable pain stress

Rats that received inescapable electric shocks for 3 weeks still showed reduced dopamine release in the nucleus accumbens weeks after the last stressor.50 In the mPFC, the dopamine and serotonin levels that were still reduced 3 days after the last stressor were restored (serotonin) or increased (dopamine) after 14 days.

Repeated stressors such as tail tweaking facilitate the acquisition of self-administration of psychostimulants such as cocaine and amphetamine.15

11.2.4.3. Dopamine changes due to chronic psychosocial stress

Chronic stress reduces the dopaminergic activity of the striatum in the long term. Institutional neglect, early childhood stress or maltreatment inhibit striatal reward function, which is dopaminergically mediated.51525354 Long-term exposure to psychosocial stress correlates with downregulation of:30

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

One study found that in subjects with low long-term exposure to psychosocial stress, dopamine synthesis increased during acute stress, while in subjects with long-term exposure to psychosocial adversity (in the sense of an accumulation of lifelong 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.30

In rats, psychosocial stress 4 times within 10 days caused a sensitization of the dopamine stress response, while chronic 5-week psychosocial stress caused a flattening of the dopamine stress response in the nucleus accumbens.55

Social isolation after a single episode of social stress causes reduced DAT binding in the striatum.56 Chronic social stress reduces the number of DAT in the striatum.57
Social stress decreased the density of DAT in the dorsolateral putamen of the striatum, repeated social stress in the nucleus accumbens of the striatum, both from 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 nucleus accumbens of the striatum after a 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.58

Chronic social stress leads to reduced59 in female cynomolgus monkeys, unchanged60 dopamine D2 receptors in male cynomolgus monkeys and increased susceptibility to cocaine addiction.

Chronic immobilization stress, such as repeated stress from social defeat, increases both spontaneous tonic and phasic burst firing of dopamine neurons in the VTA.49

11.2.4.4. Dopamine changes due to chronic unpredictable mild stress (CUMS)

Chronic unpredictable mild stress (CUMS) causes downregulation of the dopaminergic mesolimbic pathways with a reduction in dopamine levels in the nucleus accumbens, resulting in reduced sensitivity to rewards and anhedonic behaviors.27 With
* This corresponds to the changes in reduced dopamine levels and desensitized reward expectation known in ADHD. ⇒ Neurophysiological correlates of reward in ADHD In contrast, acute stress increases the dopamine level (also) in the nucleus accumbens during reward anticipation in healthy individuals.61

The results on dopamine changes caused 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 decreased somewhat after 14 days, but was still very strong compared to controls, as was the anhedonic escape deficit. in the mPFC was found by microdialysis62

  • 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 reduction in basal extraneuronal serotonin levels on day 3, but not on day 14

A 7-day CUMS exposure reduced basal as well as accumulated extracellular dopamine and serotonin levels in the nucleus accumbens shell and in the mPFC (microdialysis).62

Chronic unpredictable mild stress (CUMS) over a period of 14 days or 30 days showed no effect on dopamine levels in the nucleus accumbens or PFC (microdialysis), but led to weight loss in different rat strains.6364
5 weeks of CUMS induced anhedonia and increased DA levels in the nucleus accumbens, but not in the dorsal striatum (fast cyclic voltammetry / HPLC).65 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.66

7 to 9 weeks of chronic unpredictable mild stress, such as that used as a model of depression in animals, was treatable with the dopamine D2 agonist pramipexole (SND-919).67
8 weeks of CUMS caused a decrease in D2 receptor binding in the limbic forebrain, but not in the striatum. 5 weeks of imipramine completely abolished this. In non-stressed animals, imipramine decreased D1 receptor binding in the limbic forebrain and striatum. In stressed animals, however, 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, less from changes in receptor affinity.68

16 days CUMS69

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

Chronic food restriction leading to weight loss of 20-30% (which is rather an intense stressor) reduced basal extracellular dopamine levels in the nucleus accumbens by up to 50%, but not in the dorsal striatum (in vivo microdialysis).70

An optogenetic inhibition of VTA dopamine neurons71

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

8 to 12 weeks of CUMS decreased the normal burst activity of VTA dopamine neurons without altering the mean firing rate71 and the percentage of spikes in bursts72. 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 influences the dopamine response to external stimuli.72

HCN channels (which mediate a depolarizing cation influx, Ih) appear to influence the excitability of VTA dopamine neurons. The population activity, frequency of tonic and frequency of burst firing of VTA dopamine neurons decreases when Ih is reduced in CUMS-exposed mice. In conjunction with the decrease in Ih, silencing of the HCN2 gene in the VTA (via RNA interference) leads to depressive and anxiety-like behavior, while overexpression of HCN2 in the VTA prevented CUMS-induced depressive behavior.73
The excitability of VTA dopamine neurons is therefore crucial for the regulation of CUMS-induced depressive behavior.8

CUMS and DeltaFosB (ΔFosB)

Acute EMS increased c-Fos and FosB significantly and DeltaFosB (ΔFosB) weakly in the PFC and nucleus accumbens.
10 days of CUMS abolished the induction of c-Fos, reduced the induction of FosB and strongly increased DeltaFosB levels.47 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.74
CSDS increased the induction of DeltaFosB75

  • in mice susceptible to depression
    • in D2-MSN
      • in the nucleus accumbens core
      • in the nucleus accumbens shell
      • in the dorsal striatum
  • in resilient mice
    • in D1-MSN
      • in the entire striatum
11.2.4.5. Chronic stress impairs working memory due to dopamine deficiency via D1 receptor

While acute stress impaired the executive functions located in the dlPFC via increased dopamine levels,76 chronic stress caused reduced dopamine levels in the PFC, which impaired the function of the working memory in the dlPFC and thus the executive functions. Chronic stress induced a significant reduction in dopamine transmission and an increase in dopamine D1 receptor density in the PFC and at the same time impaired 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 cause an impairment of working memory through dopamine deficiency in the PFC via the D1 receptor.77

11.2.4.6. Chronic severe stress reduces dopamine levels

While exposure to mild stressors increased dopaminergic activity, severe chronic stressors decreased dopaminergic activity.49

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

Only some animals exposed to CSDS react with stress.
The susceptible (depressive) 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, while these remained unchanged in resilient animals78
Optogenetic induction of phasic firing of VTA dopamine neurons led to 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.79
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.8

In mandarin voles, 14 days of CSDS (significantly stronger) and emotional stress (weaker, but perceptible) had an effect compared to non-stressed animals, regardless of sex:80

  • Reduced density of dopamine D2 receptors
  • Reduced density of serotonin 1A receptors in the ACC
  • Reduced density of oxytocin receptors
  • Reduced comforting behavior (fur care)
  • Increased anxiety-like behavior

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

11.2.4.8. Dopamine changes due to repeated restraint stress

Repeated restraint stress alters the response of the mesolimbic DA system to a stressor.15

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