Neurotransmitters during stress

Neurotransmitters are important factors in the development and mediation of stress within the body.

• 1. Neurotransmitters that activate the stress systems
• 2. Disorders of the dopamine system during stress
  • 2.1. Different types of stress cause different dopamine effects
    • 2.1.1. Mild/severe - short/long - early/late stress
    • 2.1.1.1. Mild stress
    • 2.1.1.2. Short intense stress
    • 2.1.1.3. Chronic stress
    • 2.1.2. Different stressors
      • 2.1.2.1. Psychological stress
      • 2.1.2.2. Injuries and infections
      • 2.1.2.3. Repeated infliction of pain
      • 2.1.2.4. Birth stress
      • 2.1.2.5. Hypotension
      • 2.1.2.6. Conditioned stress
  • 2.2. Dopaminergic neurophysiological correlates of various stress responses
• 3. Noradrenaline, adrenaline and stress
• 4. Serotonin and stress
  • 4.1. Serotonin deficiency and stress
  • 4.2. Serotonin transporters and stress
• 5. Histamine and stress
• 6. The stress hormones CRH, cortisol and stress
• 7. Stress/ADHD symptoms due to too high or too low catecholamine levels
  • 7.1. Optimal neurotransmitter levels = optimal information transmission
  • 7.2. Stress/ADHD symptoms due to increased catecholamine levels (DA / NE)
    • 7.2.1. Acute stress increases dopamine levels in the mPFC, striatum and nucleus accumbens
    • 7.2.2. Mild acute stress = slight increase in NE/DA = increased cognitive performance
    • 7.2.3. Severe acute stress = strong increase in NE/DA and cortisol = reduced cognitive performance
      • 7.2.3.1. High noradrenaline level blocks PFC
      • 7.2.3.2. High cortisol levels block PFC
      • 7.2.3.3. Details
    • 7.2.4. PFC and amygdala - stress phenotypes
    • 7.2.5. Dopamine for stress and ADHD
  • 7.3. Stress/ADHD symptoms due to low catecholamine levels (DA / NE)

1. Neurotransmitters that activate the stress systems¶

The most important neurotransmitters that activate the stress systems of the CNS include¹

• from the locus coeruleus (A1/A2) and in the autonomic nervous system
  • Noradrenaline
• from the hypothalamus
  • AVP
  • CRH
• peptides derived from pro-opiomelanocortin
  • a-melanocyte stimulating hormone
  • ß-endorphin
• from the raphe nuclei in the midbrain
  • Serotonin
• from the posterior hypothalamic histaminergic system
  • Histamine

2. Disorders of the dopamine system during stress¶

Stress directly activates the dopaminergic system in the brain (CNS),² which is centrally impaired in ADHD.

A meta-analysis of a large number of studies showed that dopamine levels and dopamine metabolism increase during acute stress, particularly in the PFC, but less so in subcortical areas.³⁴
Stress causes a high release of dopamine, which activates D1 receptors, which in turn activate protein kinase A and CREB, leading to functional impairment of the PFC.⁵⁶

Acute stress increases DA levels in healthy rats

• In the mPFC by 95 %
• In the nucleus accumbens by 39 %
• In the striatum by 25 %⁷

In stress responses, dopamine is mainly projected from the ventral tegmentum to the PFC and nucleus accumbens, with projection to the PFC being particularly stress-sensitive.⁸⁹⁴

• Dopamine plays a role in the hedonic and reward aspects of stress.
• The effects of stress on sexual activity and appetite as well as on the affinity for drug abuse are likely to be mediated by the dopamine system.
• Dopamine increases the ability of neuronal information processing and thus the learning and information processing in relation to the stressor that has occurred.
• The amygdala (the central nucleus) influences dopamine neurotransmission in the PFC. Lesions of the central amygdala block stress-induced dopamine release in the PFC. An infusion of AMPA into the central nucleus of the amygdala causes a rapid increase in dopamine in the PFC and (as a result) increased arousal.¹⁰¹¹ This is consistent with the role of the amygdala in coordinating neuronal systems to regulate behavior under stress.

Acute stress activates nigrostriatal dopamine neurons in two ways:¹²
- dopamine release through glutamatergic input to the dopamine cell bodies, which increases the firing rate of dopamine neurons
- dopamine synthesis is accelerated locally at the level of the dopamine terminal, which replaces the used dopamine
Thus, endogenous glutamate does not appear to influence dopamine release in the neostriatum, but glutamatergic projections influence dopamine synthesis via a direct cortico-striatal pathway.
Stress increases dopamine synthesis in the neostriatum. Striatal administration of NMDA or AMPA/kainate receptor antagonists attenuated this increase¹³, but administration into the substantia nigra did not.¹²

Stress inhibits all “uptake 2” transporters via the released corticosteroids (secured: by corticosterone). The uptake 2 transporters (PMAT, OCT 1 to OCT3) have a higher dopamine reuptake capacity than the uptake 1 transporters DAT and NET, with a lower affinity. Stress thus increases extracellular dopamine (and noradrenaline) through reduced uptake-2 transporter reuptake.
The uptake 2 transporters differ in their sensitivity to corticosterone depending on the species and tissue preparation.¹⁴¹⁵

• OCT3 is more sensitive to corticosteroids than OCT1, OCT2 and PMAT
  • OCR3 shows IC50 values in the physiological range for corticosterone
• OCT3 therefore acts as a critical mediator of stress and corticosteroid effects on neuronal and glial physiology and behavior

OCT3 mediates a strong modulatory influence of stress on the effects of noradrenaline, dopamine, serotonin and histamine via the stress-induced increase in glucocorticoid hormones in a rapid, non-genomic manner.¹⁶
The deactivation of OCT1¹⁷ and OCT3¹⁸ by corticosterone occurs

• fast
• through direct interaction of corticosterone with the transporter at specific sites

The main description of the PMAT can be found at Dopamine reuptake by the plasma membrane monoamine transporter (PMAT) in the article *Dopamine reuptake, dopamine degradation*and the main presentation of OCT follows on from there.

Chronic stress causes an increased increase in extracellular dopamine and noradrenaline in the PFC in response to a new acute stressor,^{1219 20 21} but not in the nucleus accumbens or neostriatum.

These findings are consistent with

• our finding that ADHD symptoms resemble those of chronic severe stress
• our assumption of dopaminergic hyperfunction in the PFC with simultaneous dopaminergic hypofunction in the striatum and nucleus accumbens in ADHD

2.1. Different types of stress cause different dopamine effects¶

Not all stress is the same. Depending on the type of stress, different effects are triggered on the dopamine system.

The types of stress differ according to:

• Duration and intensity of stress
  Mild stress slightly increases the dopamine level (as well as the noradrenaline level) in the PFC and thus improves cognitive performance. Severe stress increases the dopamine level and the noradrenaline level in the PFC extremely and causes the PFC to shut down. Behavior control is outsourced to other parts of the brain.
• Type of stressor Each stressor has its own specific effects on the neurotransmitters. Different stressors are, for example
  • Psychological stress
  • Physical pain
  • Injuries
  • Cold
  • Heat
  • Diseases

All stress symptoms have their own neurophysiological correlates.
A neurophysiological correlate means that a specific activity or change occurs in a certain area of the brain together with the symptom.

2.1.1. Mild/severe - short/long - early/late stress¶

2.1.1.1. Mild stress¶

• Low stress levels are primarily processed in the mesoprefrontal system. Other ascending dopaminergic systems are not influenced by this.²²⁴ This could be due to a significantly lower number of inhibitory D2 autoreceptors in the mesoprefrontal area and extensive excitatory signals to the ventral tegmentum.
• Mild stress increases dopamine, serotonin and noradrenaline metabolism²³ in the mPFC²⁴
  • Serotonin influences
    • The hypothalamus (part of the HPA axis / stress regulation axis)
    • The amygdala, which activates the HPA axis
    • The hippocampus, which inhibits the HPA axis.
• Mild (not too prolonged) stress causes slightly increased noradrenaline and dopamine levels in the PFC.
• Slightly elevated noradrenaline and dopamine levels increase the activity of the PFC and thus its cognitive and executive performance.
• Highly elevated dopamine and/or noradrenaline levels switch off the PFC and shift behavioral control to other areas of the brain.
• Low to moderate levels of stress increase extracellular²⁵ dopamine levels in the nucleus accumbens²⁶²⁷ , but only in the NAc shell, not in the NAc nucleus²⁸²⁹ and PFC²⁶²⁷ , while high levels of stress (intense, chronic or unpredictable) decrease dopamine levels³⁰³¹ . The increase in dopamine levels is greater in the PFC than in the striatum; within the striatal complex, it is greatest in the NAc shell.³²²⁵

2.1.1.2. Short intense stress¶

• Short-term intense stress massively increases the dopamine level in the PFC

2.1.1.3. Chronic stress¶

• Chronic stressors (chronic cold exposure, chronic mild stress) have been shown to decrease population activity, i.e. the number of active neurons, but only in the medial and central VTA, not in the lateral VTA, and without decreasing the firing frequency. Bursts were slightly increased during chronic cold exposure.
  Stressors that increase dopamine firing also increase the risk of addiction and addiction relapses, which are prevented by blocking dopamine receptors.
• Chronic early childhood stress reduces the dopamine level in the nucleus accumbens through downregulation.³³
• Dopamine in the mPFC normally suppresses mesolimbic dopamine transmission. However, this is no longer successful under extreme or unpredictable stress. Dopamine innervation also appears to be important for stress-induced activation of neurons in the stria terminalis (anterolateral BNST).³⁴⁴ which are involved in both the activation of higher-order stress-dependent circuits and the generation of coping behavior.
• Increased dopamine levels in the mPFC lead to a reduction in dopamine levels in the nucleus accumbens in the striatum (reinforcement center), which in the long term could lead to overactivation of the dopamine transporters by upregulation, which is a major problem in ADHD.
• Chronic stress leads to a reduction in the dopamine level in the PFC via downregulation (increase in the number of dopamine transporters and dopamine receptors).
• In chronic stress, the reduced dopamine level in the PFC after downregulation is nevertheless associated with
  • With overexcitation of the PFC
  • With a reduction in dopamine levels in the nucleus accumbens in the striatum
• Chronic early childhood stress (daily hand-holding in rats, handling) leads to increased dopamine metabolism in the nucleus accumbens in adulthood. This results from a loss of inhibitory control by the right mPFC due to a dopamine deficiency found there. The dopamine deficiency in turn correlates with an increase in the number of dopamine transporters.³⁵
• The long-term nature (chronification) of stress and the degree of control over the stressor changes dopamine-dependent behaviors and the activation of afferents to the nucleus accumbens.³⁶⁴
• While stress-induced dopamine release in the neostriatum is mediated by a glutamate effect on the dopamine cell body, stress-induced dopamine synthesis in the neostriatum is mediated by a glutamate effect on the dopamine nerve terminals¹²
• Acute stress increases dopamine metabolism and dopamine release more in the PFC (+ 90 %) than in subcortical areas (nucleus accumbens + 40 %, neostriatum + 30 %)¹²
• Previous chronic stress intensifies the reaction to an acute new stressor¹²
  • Only in mesocortical dopamine neurons
  • Not in the subcortical areas
• Stress increases DOPAC in tissue³⁷ and c-fos-expressing neurons³⁸
  • In VTA
  • But not in substantia nigra

2.1.2. Different stressors¶

Each stressor has its own specific effect on dopamine.³⁹

• Most stressors increase extracellular dopamine through an increase in dopamine efflux, an increase in neuronal activity in total firing rate and/or bursts:²⁵
  • Food restriction/withdrawal
  • Bondage stress
  • Social defeats
  • Cold swimming

2.1.2.1. Psychological stress¶

• Mental stress apparently only activates the dopaminergic D2 receptor system.⁴⁰
• Psychosocial stress
  • Increases the number of D2 receptor binding sites in the hippocampus.⁴¹
  • Reduces the binding of the ligand 3 H-WIN 35,428 for the dopamine transporter in the striatum after 4 weeks.⁴⁰
  • Chronic psychosocial stress leads to a “shrinkage” of the dendrites of pyramidal neurons in the CA 3 region of the hippocampus.⁴²
  • Chronic social stress reduced in mice⁴³
    • In the hypothalamus: dopamine, noradrenaline and serotonin levels
    • In the PFC: serotonin and dopamine levels
  • Alcohol in the striatum did not increase dopamine levels in the defeated mice, while dopamine levels increased in non-defeated mice
• Taking in the hand (of mice; handling)
  • Increases dopamine levels
    • In the mPFC⁴⁴⁴⁵
    • In the nucleus accumbens (albeit low)⁴⁵
  • Does not change dopamine levels
    • In the striatum⁴⁵
• Acute physical constriction (fixation)
  • Increases dopamine in the mPFC and in the nucleus accumbens (mesolimbic dopamine system)⁴⁶ and acetylcholine in the hippocampus.⁴⁷
  • The dopamine increase in the mPFC and nucleus accumbens as well as the acetylcholine increase in the hippocampus also occur after the subsequent release, which is why this could be a correlate of emotional arousal due to a sudden change in environmental influences.⁴⁷⁴⁶
  • Increases the concentrations of the dopamine metabolite DOPAC in the PFC and nucleus accumbens⁴⁸
  • Induces Fos immunoreactivity in dopamine neurons of the ventral tegmentum (VTA), but not in the substantia nigra⁴⁹
• Stress due to new environment
  • Increases dopamine levels in the right PFC⁵⁰
• Anxious behavior in the open environment
  • Correlates with increased dopamine levels in the right PFC⁵¹
• Escape behavior in response to shocks
  • Correlates with increased dopamine levels in the right PFC⁵²

2.1.2.2. Injuries and infections¶

• Injuries and infections activate the D1 and D2 receptor system⁴⁰

2.1.2.3. Repeated infliction of pain¶

• Electric shocks
  • Activate the mesolimbic dopamine system⁴⁷⁴⁶
  • Increase FOS expression
    • In prelimbic and infralimbic cortexes⁵³
    • In tyrosine hydroxylase-labeled neurons of the ventral tegmentum (VTA)⁵³
• Tail crushing in mice
  • Increase dopamine levels

    • In the mPFC⁴⁵

    • In the nucleus accumbens (albeit low)⁴⁵

    • Do not change dopamine levels

      • In the striatum⁴⁵

2.1.2.4. Birth stress¶

• Oxygen deprivation during birth leads to increased dopamine metabolism in the nucleus accumbens in adulthood. This results from a loss of inhibitory control by the right medial prefrontal cortex (PFC) due to a dopamine deficiency found there. The dopamine deficiency in turn correlates with an increase in the number of dopamine transporters.³⁵

2.1.2.5. Hypotension¶

• Increases the dopamine level in the mPFC⁵⁴⁴

2.1.2.6. Conditioned stress¶

• Increases dopamine and serotonin levels in the brain
  • MPFC²⁴⁵⁵⁴
  • Lateral PFC⁵⁵⁴
  • Nucleus accumbens⁵⁵⁴
• Does not change dopamine levels in
  • Perirhinal cortex⁵⁵⁴
  • Cingulate cortex⁵⁵⁴
  • Basolateral amygdala⁵⁵⁴
  • Striatum⁵⁵⁴
• Acute conditioned stress should only increase the noradrenaline level in the mPFC, but not the dopamine level.⁵⁶
• Lesions of the left and right amygdala prevent an increase in dopamine in the mPFC and other stress responses to conditioned stress.²⁴

2.2. Dopaminergic neurophysiological correlates of various stress responses¶

Different stress responses have different dopaminergic neurological correlates.

• Jumpiness
  • Is controlled by increased dopamine in the dorsal striatum and by stimulation of the (dopamine-producing) substantia nigra pars compacta.²
  • Dopamine release in the mesolimbic system (nucleus accumbens = ventral striatum) through electrical stimulation of the ventral tegmentum promotes **aversively motivated learning
• Learning from stressful experiences
  • Drug blockade of dopamine receptors in the amygdala prevents this.²
• Maintaining attention to solve problems
  • Is controlled by the dorsolateral PFC.⁵⁷
• Selective attention (directing attention)
  • Is controlled by the dorsal anterior cingulate cortex.⁵⁷
• Hyperactivity
  • Is organized by the OFC⁵⁸ and
  • The prefrontal motor cortex.⁵⁷
• Impulsiveness
  • Is organized by the OFC and the
  • Cortico-striatal-thalamocortical loop (cortex-striatum-thalamus control loop).⁵⁹
• Disorder of social behavior (Conduct Disorder, CD)
  • Controlled by a network of the ventromedial PFC and the limbic system⁶⁰
• Oppositional defiant behavior (ODD)
  • Controlled by a network of the ventromedial PFC and the limbic system⁶⁰
• Aggression
  • Controlled by a network of the ventromedial PFC and the limbic system⁶⁰
• Anxiety disorders
  • Controlled by a network of the ventromedial PFC and the limbic system⁶⁰
• Bipolar Disorder
  • Controlled by a network of the ventromedial PFC and the limbic system⁶⁰
• Thought blocks, PFC deactivation
  • Strong stimulation of D1 receptors by stress may serve to “turn off” the PFC so that posterior cortical and subcortical structures can regulate behavior.⁶¹

3. Noradrenaline, adrenaline and stress¶

In the CNS, stress is primarily modulated by noradrenaline⁶²

• Moderate noradrenaline levels
  • Strengthen the function of the PFC
• High noradrenaline levels
  • Switch off the PFC (which impairs analytical thinking)
  • Strengthen the sensorimotor and affective regions of the brain (which intensifies perception and emotion)

Acute stress had a primary noradrenergic effect on the postsynaptic response and reduced the phasic release of noradrenaline⁶³

The activation of microglia by stress appears to be mediated by noradrenaline via β1- and β2-adrenoceptors, but not via β1-AR β3-adrenoceptors or α-adrenoceptors.⁶⁴

Second graders showed increased cortisol levels on exam days and simultaneously decreased adrenaline and noradrenaline levels. The individual differences in secreted hormones were significantly related to personality variables observed in the classroom as well as the effects of academic stress:⁶⁵

• Social approach behavior correlated with higher cortisol and adrenaline levels
• Fidgeting correlated with low adrenaline levels
• Aggressiveness correlated with high noradrenaline levels
• Inattention correlated with low noradrenaline levels

4. Serotonin and stress¶

The ascending serotonergic pathways, which originate in the midbrain (nuclei raphe), accompany the central stress response derived from the locus ceruleus by releasing serotonin.¹

There is a connection between serotonin and sensitivity to stress. However, the results are heterogeneous and the causes and correlations are still unclear.⁶⁹
There is a connection between serotonin and cortisol levels.
Stress increases serotonin levels in healthy people⁷⁰ as well as noradrenaline, dopamine and cortisol levels⁷¹.
Acute stress, on the other hand, is said to reduce serotonin production in the dorsal raphe nuclei, while fluoxetine stimulates serotonin production.⁷²
Severe, life-threatening stress appears to increase the function and expression of serotonin 2-A receptors, as found in PTSD. Paradoxically, the PTSD medication 3,4-methylenedioxymethamphetamine acts as a serotonin 2-A receptor agonist.⁷³

The adrenal cortex is removed so that cortisol can no longer be released,

• This changes the release of serotonin in the dorsal raphe nuclei (DRN)
  • Not for nominal conditions
  • However, it decreased under stress
    Stimulation of the glucocorticoid receptors in the DRN then prevents the stress-induced serotonin blockade.⁶⁹
• Avoids unpredictable chronic stress⁷⁴
  • The depression that normally occurs
  • But not the fear that normally arises
    • In the development of which the mineralocorticoid receptor is involved
    • Which is closely linked to cell proliferation in the hippocampus
• This increases serotonin levels and TPH2 expression in the hippocampus in response to chronic unpredictable stress.⁷⁴

Repeated stress increases serotonin production more than single stress⁷⁵ and leads to apical dendrite reduction in the medial PFC, which reduces the number of excitatory postsynaptic events mediated by serotonin and orexin/hypocretin. Cortisol did not result in these Consequences. A GR antagonist given before stress avoided the reduction of serotonin-mediated excitatory postsynaptic events, but not those mediated by orexin/hypocretin.⁷⁶

Chronic stress increases cortisol levels through the release of vasopressin rather than CRH.⁷⁵

Cortisol increases the serotonin level in the amygdala and in the PFC⁷⁷ as well as in the hippocampus.⁷⁵ This is probably due to activation of the glucocorticoid receptors. This is because inhibition of monoamine oxidase increases the serotonin level, while a reduction in the cortisol level prevents this increase in serotonin (caused by monooxidase inhibition).⁷⁸ This effect of cortisol lasts a long time (as with SSRIs) and presumably occurs through desensitization of the serotonin 1-A autoreceptor.⁷⁹ However, the desensitization of the serotonin 1-A autoreceptor caused by SSRIs such as fluoxetine appears to act independently of the glucocorticoid receptor.⁸⁰

Removal of the adrenal gland (in whose “cortex” cortisol is produced) causes⁶⁹

• Unchanged serotonin transporter expression in the dorsal raphe nuclei (where serotonin is produced)
• Unchanged [3H]cyano-imipramine binding to serotonin transporters in the dorsal raphe nuclei
• Unchanged [3H]citalopram binding to serotonin transporters of the mesencephalon (midbrain)
• Reduced serotonin reuptake in the mesencephalon (midbrain)
• No change in serotonin transports in the dorsal raphe nuclei, medial raphe nuclei or in the mesencephalon with simultaneous long-term administration of MR- and GR-binding corticoids

In healthy rats, causes⁶⁹

• Acute corticosterone administration unchanged serotonin reuptake in the mesencephalon (midbrain)
• A long-term infusion of dexamethasone (a stronger GR agonist than MR agonist)
  • Reduces serotonin transporter expression in the midbrain
  • But does not influence them in the hippocampus or PFC.
• Short-term stress has no influence on serotonin transporter density in the midbrain
• Prolonged stress (21 days)
  • Increases [3H]cyano-imipramine binding in the dorsal raphe nuclei
  • Increases (to a lesser extent) serotonin transporters in the medial raphe nuclei

Serotonin interacts extensively with BDNF in relation to⁸¹

• Aggression
• Depression
• Drug addiction
• Suicidal tendencies
• Stress regulation
• Brain plasticity

4.1. Serotonin deficiency and stress¶

Serotonin deficiency via deprivation of the serotonin precursor tryptophan activates the HPA axis in the same way as another stressor, but together with this it did not cause any synergistic stress axis effects.⁸²⁸³

SSRI administration reduced PTSD symptom severity in children and adults in one study.⁸⁴

Serotonin deficiency is clinically evident in connection with⁸¹

• Depression
• Fear
• Impulsiveness
• Suicidal tendencies
• Schizophrenia.

4.2. Serotonin transporters and stress¶

Reduced serotonin transporter binding affinity correlates with an increased cortisol stress response and increased anxiety.⁸⁵

Various studies have been carried out on the serotonin transporter genotype

• No significant influence on cortisol stress response or mood⁸⁵
• That the 5-HTTLPR short/short genotype correlates with a higher cortisol stress response
  • In young adults to psychosocial stress⁸⁶
  • In newborns to a physical stressor⁸⁷
• That the group of 5-HTTLPR short genotypes (SS, SLG, LGLG, SLA, LGLA) correlated with a greater frequency of early childhood stress experiences in the first 5 years of life compared to 5-HTTLPR long/long (LALA) in younger adults, but not in children.⁸⁸
• Twins who had suffered bullying had a higher serotonin transporter methylation at the age of 10 than their twin siblings without bullying experience. Twins with later (!) bullying experience already showed an increase in methylation at the age of 5, i.e. before this (!) bullying experience, compared to their non-bullied twin siblings. Children with higher serotonin transporter methylation levels showed a flattened cortisol stress response.⁸⁹ This could be related to the fact that people with impairments (such as ADHD) are more likely to be victims of violence. ADHD increased the likelihood 2.7-fold, according to one study.⁹⁰
• That the group of 5-HTTLPR short genotypes (SS, SLG, LGLG, SLA, LGLA) in combination with many early childhood stress experiences in the first 5 years of life
  • Correlates with a high cortisol stress response to the TSST.⁸⁸ Similar results were found in several other studies.⁹¹⁹²⁹³
• That 5-HTTLPR long/long (LALA) in combination with few early childhood stress experiences in the first 5 years of life
  • Correlates with a high cortisol stress response to the TSST⁹¹
  • Which another study only found in younger adults⁸⁸
  • While another study found no correlation⁹³

5. Histamine and stress¶

The posterior hypothalamic histaminergic system supports the central stress response derived from the locus coeruleus by releasing histamine.¹

6. The stress hormones CRH, cortisol and stress¶

CRH and cortisol are not neurotransmitters, but hormones that are produced by the hypothalamus as the first increment of the HPA axis (CRH) and the adrenal cortex as the last increment of the HPA axis (cortisol).
As the HPA axis is essential for understanding stress and ADHD, we refer here to the detailed description at ⇒ HPA axis The HPA axis / stress regulation axis and ⇒ Cortisol in ADHD.

Older adults

• With a low number of stressful life experiences in the first 15 years of life showed the highest cortisol stress response⁸⁸
• With a high number of stressful life experiences in the first 15 years of life showed the lowest cortisol stress response⁸⁸

While some authors⁸⁸ regard a low cortisol stress response as a measure of a healthy reaction, we ask ourselves whether a medium cortisol stress response is not healthy and whether a particularly low cortisol stress response, as well as an excessive cortisol stress response, is a sign of a stress system imbalance, as is also the case with the cortisol stress response.

7. Stress/ADHD symptoms due to too high or too low catecholamine levels¶

7.1. Optimal neurotransmitter levels = optimal information transmission¶

Optimal transmission of information between brain synapses requires an optimal level of the respective neurotransmitters. A neurotransmitter level that is too low leads to an almost identical signal transmission disorder as a neurotransmitter level that is too high (reversed-U theory).^{94959697969899100101102103104105}

For optimal signaling, the pyramidal cells of the PFC require moderate stimulation of D1 receptors by dopamine and α2A receptors by norepinephrine. Dopamine binding to D1 receptors reduces the noise of the input signal in the PFC by reducing signals from unneeded external sources, while noradrenaline amplifies the incoming signal from external sources via α2A receptors.¹⁰⁶

Increased DA and NE levels cause additional occupancy of receptors, which reduces attention. Reduced DA and NE levels result in all incoming signals being identical, which reduces concentration on individual tasks.

A DA and/or NE level that is too high or too low therefore leads to very similar symptoms due to suboptimal signal transmission in the PFC.¹⁰⁷

Therefore, a medication that increases neurotransmitter levels and works well at low doses can, at higher doses, cause the very symptoms that it avoids at low doses. This is why it is a mistake to start medication for ADHD at the target dosage or to dose it quickly. It is better to start the titration phase (medication phase) particularly slowly and low than too quickly and too high.

7.2. Stress/ADHD symptoms due to increased catecholamine levels (DA / NE)¶

7.2.1. Acute stress increases dopamine levels in the mPFC, striatum and nucleus accumbens¶

Stress increases dopamine levels in healthy rats

• In the mPFC by 95 %
• In the nucleus accumbens by 39 %
• In the striatum by 25 %¹⁰⁹¹¹⁰

Stress involves a phasic (i.e. short-term) increase in dopamine levels.¹¹¹

7.2.2. Mild acute stress = slight increase in NE/DA = increased cognitive performance¶

The mild stress reactions of the autonomic nervous system are mediated by acetylcholine and adrenaline.

In the central nervous system (brain), slight increases in dopamine and/or noradrenaline levels cause increased performance of the PFC (except in carriers of the COMT Met158Met gene polymorphism).^{112113114115116}

If this does not solve the problem (the stressor is not eliminated), dopamine and noradrenaline levels continue to rise. High noradrenaline levels activate the HPA axis (stress axis), which only comes into action when stress is difficult to cope with.

7.2.3. Severe acute stress = strong increase in NE/DA and cortisol = reduced cognitive performance¶

7.2.3.1. High noradrenaline level blocks PFC¶

In contrast to mild increases in noradrenaline, which stimulate the PFC, strong increases in noradrenaline switch off the PFC and shift behavioral control to posterior brain regions.^{62117118119120121122}

This should correspond to the effect described by Dietrich¹²³ with reference to Mobbs et al¹²⁴ as posteriorization.

7.2.3.2. High cortisol levels block PFC¶

High cortisol levels, as they occur particularly in ADHD-I and SCT during acute stress, additionally stimulate the noradrenaline α1 receptors in the PFC, via which noradrenaline already impairs the function of the PFC and working memory. The simultaneous addressing of these receptors by noradrenaline and cortisol intensifies this effect.¹²⁵
In addition, the shift of control from cognitive brain regions (PFC and hippocampus) to more behavioral brain regions (such as aymgdala and dorsal striatum) is regulated by the cortisolergic mineralocorticoid receptors (MR) and glucocorticoid receptors (GR).¹²⁶

Cortisol, which is often elevated as a stress response in ADHD-I and presumably also SCT, blocks the retrieval of declarative (explicit) memory via the glucocorticoid receptors (GR) in the PFC and hippocampus. The non-declarative (implicit, intuitive) memory is not affected.¹²⁷ This could explain the thinking and memory blocks often associated with ADHD-I and also why people with ADHD-I are often said to have a higher level of intuition. In any case, it would stand to reason that the shift in the focus of memory skills leads to a shift in problem-solving patterns. Trappmann-Korr calls this “holistic” perception. However, our own data collection so far shows that a self-assessment of being intuitive is present in 69% of people with ADHD-HI and only in 60% of people with ADHD-I. (n = 1,100, as of August 2019)
It is likely that not only the retrieval (remembering), but also the acquisition (learning) and memory consolidation (long-term storage) of information is impaired. Consolidation occurs particularly during sleep in the first half of the night, which is characterized by particularly low basal cortisol levels. Consolidation can be prevented by low cortisol levels.¹²⁷

7.2.3.3. Details¶

Since the PFC controls the HPA axis, it is additionally disinhibited by the loss of control by the PFC.
Other voices distinguish between short-term stress, which increases the cognitive performance of the PFC, and long-term stress, which reduces it,¹²⁸ which should be the same result.

Slightly elevated catecholamine levels activate postsynaptic alpha2A adrenoceptors (by noradrenaline) and D1 receptors (by dopamine) and thus improve prefrontal regulation of behavior and attention, while strongly elevated catecholamine levels worsen prefrontal functions by stimulating noradrenergic alpha1 adrenoceptors and (excessively) dopaminergic D1 receptors.¹²⁹¹⁰¹
Alpha1 adrenoceptors are less sensitive than alpha2A adrenoceptors and therefore only respond to higher noradrenaline levels. If the noradrenaline level is so high that it can activate not only the alpha2a but also the alpha1 adrenoceptors, the alpha1 adrenoceptors inhibit the cognitive performance of the PFC.^130119131132
See also the description of adrenoceptors = noradrenaline receptors at ⇒ Noradrenaline.

Alpha1-adrenoceptor antagonists (blockers) are used to treat PTSD.

Increases in cortisol are associated with stress-induced release of noradrenaline and α1-adrenergic receptor activation.¹³⁵¹³⁶
The increase in cortisol levels after stress is mediated by activation of the adrenergic system and the α1-adrenergic receptors, in that a strong increase in noradrenaline levels activates alpha1-adrenoceptors in the hypothalamus and thus leads to the release of the stress hormone CRH, which activates the further increments of the HPA axis (release of ACTH and cortisol).^135137136138
CRH reduces the performance of the PFC (especially working memory) in a dose-dependent manner. CRH antagonists neutralize this effect.¹³⁹¹⁴⁰

The activation of alpha1-adrenoceptors by high noradrenaline levels thus causes high cortisol levels and attention problems.¹⁴¹

The noradrenaline level in the OFC and in the amygdala correlates with the activation of the HPA axis in healthy people. In severely overweight people, however, this correlation is inverted.¹³⁸

7.2.4. PFC and amygdala - stress phenotypes¶

The activity of the PFC is inverse to the activity of the amygdala. An active PFC correlates with a less active amygdala and vice versa.¹⁴²
It is known that anxiety and depression occur more frequently in people who internalize stress, i.e. eat stress into themselves (internalizing, ADHD-I subtype) rather than acting it out (externalizing, ADHD-HI/ADHD-C). In the latter, externalizing disorders such as aggression disorders (Oppositional Defiant Disorder; Social Behavior Disorder, Borderline) predominate.

With this in mind, the fact that ADHD-I has a higher incidence of disorders associated with an activated amygdala, such as anxiety and depression, suggests that the PFC is more frequently deactivated in ADHD-I than in ADHD-HI. Together with the fact that elevations in cortisol are associated with stress-induced release of norepinephrine and α1-adrenergic receptor activation,¹³⁵¹³⁶ this leads us to hypothesize that in ADHD-I, norepinephrine release in response to acute stress may be very frequently excessive, analogous to cortisol release, which causes a more frequent shutdown of the PFC and a shift of behavioral control to subcortical brain regions, while in ADHD-HI, which is often associated with a reduced release of cortisol in response to acute stress, there should be a correlating reduced release of noradrenaline, which less frequently (and perhaps even too rarely in view of the inability to recover) leads to a downregulation of the PFC.

7.2.5. Dopamine for stress and ADHD¶

DAT knockout mice, which have almost no dopamine transporters (DAT) (i.e. they represent a kind of neurological anti-model to ADHD, in which too many DAT are present) have some symptoms like people with ADHD:¹⁴³

• Hyperactive
• Learning problems
• Memory problems

The disorders that often occur comorbidly with ADHD

• Disorder of social behavior (conduct disorder, CD)
• Oppositional defiant behavior (ODD)
• Psychosis
• Bipolar

are typically associated with extremely elevated dopamine levels in some areas of the brain.¹⁰⁷

7.3. Stress/ADHD symptoms due to low catecholamine levels (DA / NE)¶

Massive dopamine deficiency in the striatum leads to a massive disorder of drive. The interest In pleasure is reduced, while the abilityto enjoy itself is not impaired.

However, dopamine deficiency is only one way of causing the symptoms mentioned. Excess dopamine causes largely identical symptoms, as the main factor is a deviation from an optimal dopamine level for signal transmission (see 1.1. and 1.2. above).

• Rats whose ascending dopaminergic pathways were almost completely destroyed, resulting in 99% less dopamine being available, subsequently lacked the drive to consume their previously preferred sugar solution. This phenomenon was therefore caused by a lack of dopamine in the reinforcement center of the brain (striatum). The animals’ ability to perceive pleasure when they were given the sugar solution remained unchanged, as evidenced by the typical tongue movements that rats make in response to foods they find pleasant. This pleasure response could also be enhanced by hedonically activating substances (e.g. benzodiazepines) and weakened by simultaneous unpleasant stimuli.¹⁴⁴¹⁴⁵
• The neurotoxin 6-hydroxydopamine selectively destroys dopaminergic neurons. Animals treated in this way develop hyperactive behavior¹⁴⁶
  • According to other accounts, 6-hydroxydopamine has a more noradrenergic effect.¹⁴⁷ Noradrenaline is also significantly involved in ADHD.
  • Disorders of dopamine levels caused by 6-hydroxydopamine showed a major role of D4 receptors in the caudate nucleus (but not of D2 receptors) in the development of hyperactivity.¹⁴⁸
• The people with ADHD who were affected by the encephalitis epidemic from 1914 to 1917 developed typical ADHD symptoms. Children developed hyperactive motor skills, adults Parkinson’s symptoms. Encephalitis destroys the cells in the substantia nigra that produce dopamine. This cause could be reproduced in animal experiments as the trigger for the symptoms. The symptoms are therefore consequences of the dopamine deficiency.¹⁴⁹ When diagnosing ADHD, encephalitis must still be clarified as a differential diagnosis.
• Perinatal hypoxia, which leads to early childhood brain damage (FKHS), causes the dopaminergic cells in the striatum to die, reducing the dopaminergic level in the striatum by up to 70 %.
• In people with ADHD, the cells of the substantia nigra are damaged, which reduces the synthesis of dopamine by up to 90 percent. This causes motor impairments such as rigor, tremor and akinesia. Depression is many times more common in people with ADHD, which is also likely to be due to the dopamine deficiency.¹⁵⁰
• Cocaine or amphetamine abuse causes a downregulation of the body’s own dopamine synthesis. After stopping the cocaine intake, hyperactivity occurs as a withdrawal symptom due to the now too low dopamine level.¹⁵¹
• Nicotine, which is consumed earlier and more frequently by people with ADHD,¹⁵² increases the release of dopamine in nigrostriatal and mesolimbic areas and thus improves attention.¹⁵³¹⁵⁴
• Toxins such as polychlorinated biphenyls, which inhibit the synthesis of dopamine and the storage of dopamine in the vesicles and its release, thereby causing dopamine levels to be too low, also cause hyperactivity and impulsivity (in rats even at sub-toxic doses).¹⁵⁵
• Dysphoria is caused by dopamine deficiency (according to Wender-Utah, dysphoria with inactivity is a core symptom of ADHD in adults).¹⁵⁶

The fact that dopamine deficiency is involved in mediating ADHD symptoms is shown by the very good effect of drugs that result in increasing dopamine levels or mediating an improved response to dopamine. Stimulants (methylphenidate, amphetamine drugs) and atomoxetine act as dopamine reuptake inhibitors (which increase the availability of dopamine in the synaptic cleft) and stimulate dopamine production.

However, not all medications that increase dopamine levels are helpful for ADHD. The dopamine agonists L-dopa (levodopa), amantadine and piribidel, for example, have no positive effects on ADHD despite their dopamine-increasing effect.¹⁵⁷

• Levodopa is a precursor of dopamine (prodrug) that can cross the blood-brain barrier and is metabolized to dopamine in the brain.¹⁵⁸ Levodopa is helpful for Parkinson’s disease and restless legs syndrome, both of which are characterized by a lack of dopamine, but is not effective for ADHD.
• Amantadine is a weak glutamate receptor antagonist of the NMDA receptor, increases the release of dopamine and acts as a dopamine reuptake inhibitor. Its effect in Parkinson’s disease is controversial. In some cases, a weak activating effect on arousal is reported.¹⁵⁹
• Piribedil is a piperazine derivative and therefore a non-ergot dopamine agonist.
  Piribedil is an agonist of the D2 and D3 dopamine receptors and an antagonist of the α2 adrenoreceptor subtypes α2A and α2C. It is used to treat Parkinson’s disease, also in combination with levodopa.

While short-term stress without ADHD leads to an excess of catecholamines (dopamine and noradrenaline) in the PFC,¹⁴³ early long-term stress leads to a downregulation of the dopamine and noradrenaline systems. For example, chronic early childhood stress reduces dopamine levels in the nucleus accumbens.³³

Exercise-induced stress in rats causes a later downregulation of dopamine in the ventral tegmentum via noradrenaline at beta-adrenoceptors of the amygdala.¹⁶⁰

Whether there is too little or too much (tonic = long-term) catecholamine in ADHD is the subject of intense debate.¹⁶¹
The disagreement among scientists indicates that both variants occur. It is possible that the subtypes and individual symptom compositions of the respective people with ADHD differ. It is undisputed that many people with ADHD have reduced dopamine levels in the PFC and striatum.
According to current knowledge, we assume that ADHD is caused by a deficiency of dopamine and noradrenaline in the dlPFC, striatum and probably also the cerebellum.

The typical ADHD medications (stimulants and atomoxetine act as dopamine and noradrenaline reuptake inhibitors. Stimulants increase the DA and NE levels in the PFC and striatum, atomoxetine only in the PFC) increase the availability of these neurotransmitters in the synaptic cleft.