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9. Disorders of the dopamine system in ADHD

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9. Disorders of the dopamine system in ADHD

ADHD, in our view, mediates its symptoms in a manner comparable to chronic stress through dopamine and norepinephrine (effect) deficiency, among other factors.

Further, in our view, early childhood chronic stress, as well as dopamine and norepinephrine deficiencies caused genetically, epigenetically, or otherwise, can impair brain development, leading to ADHD symptoms. For more on this, see ⇒ Brain Developmental Disorder and ADHD in the chapter Emergence.

9.1. Genetic abnormalities with a dopaminergic background in ADHD

In ADHD, a striking number of polymorphisms (specific gene variants) are involved in genes that affect dopamine levels, e.g.:

  • DRD21
  • DRD31
  • DRD4
    • The 7-repeat allele of DRD4 causes the sensitivity of the D4 dopamine receptor (DRD4) to dopamine to be reduced. In subtype ADHD-I (without hyperactivity), the PFC is primarily affected.2 Against the background that hyperactivity neurophysiologically originates in the striatum and can be caused there by reduced as well as excessive dopamine levels, this would be plausible.
  • DRD5
  • DAT1
    • Dopamine transporters (DAT) bear the brunt of dopamine degradation in the striatum.
  • COMT
    • Dopamine degradation in the PFC occurs primarily by the enzyme COMT as well as NET, which reuptake more dopamine than norepinephrine in the PFC. The COMT Val/Val polymorphism causes 4 times faster dopamine degradation in the PFC. This could contribute to a dopamine deficit in the PFC, as suspected in ADHD. However, most genetic studies to date have found no correlation between variants of the COMT gene and ADHD.3 Surprisingly, one study found Val/Val improved sustained attention in children with ADHD. In contrast, Val/Met or Met/Met variants showed significantly worse sustained attention in children with ADHD than the norm values.4 This could also be explained by the fact that ADHD would be accompanied by an excess of dopamine in the PFC, since increased dopamine depletion would then bring the dopamine level into the middle range associated with optimal cognitive ability. This is because dopamine excess and dopamine deficiency are equally impairing.5. However, this conflicts with the fact that amphetamine medications, which increase dopamine levels in the PFC, can improve sustained attention in ADHD. 0.25 mg/kg amphetamine improved physiological efficiency in healthy Val/Val gene carriers (= increased dopamine depletion) and worsened it in healthy Met/Met gene carriers (slowed dopamine depletion).6 However, it is possible that such affected individuals could also be AMP nonresponders
    • Mb-COMT knockout mice (mice lacking membrane-bound COMT) show increased levels of dopamine in the striatum. This suggests that mb-COMT is also involved in dopamine degradation in the striatum.7

9.2. Alterations of the dopamine system in ADHD, chronic and acute stress

The literature suggests that ADHD is characterized by decreased levels of dopamine and norepinephrine in the PFC and striatum/nucleus accumbens,8 as is the case with chronic stress. In contrast, acute stress is characterized by increased dopamine levels in these brain regions.910 The symptoms of dopamine and norepinephrine deficiency (ADHD, chronic stress) and dopamine and norepinephrine excess (acute stress) are nevertheless partly identical and confusable. They occur when the optimal neurotransmitter level for information transmission in the brain is exceeded or undershot (inverted-U theory).8 Primarily affected are the dlPFC (working memory - executive functions), the striatum (motivation and motor inhibition) and the cerebellum (time processing).

However, there are also animal models with excessive dopamine levels that show ADHD symptoms. The DAT-KO mouse shows dramatically increased basal dopamine levels in the striatum, but phasic dopamine release in the striatum is reduced. The DAT-KO mouse (especially the heterozygous variant, in which the DAT are approximately halved) shows almost the full picture of ADHD symptoms. There are (rarely) also people without or with very much reduced DAT. However, these show other symptoms that are not ADHD-typical (e.g. early Parkinson’s dystonia) and are therefore rarely misdiagnosed with ADHD and rather with cerebral palsy. Many affected individuals die as teenagers.11 Excess extracellular dopamine leads to decreased production of dopamine (and thus decreased storage of dopamine in vesicles) and downregulation or desensitization of dopamine receptors through activation of presynaptic D2 autoreceptors, resulting in phasic dopamine deficiency and dopamine action deficiency.12

While acute and chronic stress in adulthood usually cause reversible neurotransmitter changes, repeated acute stress or chronic stress can trigger permanent damage, especially during periods of brain developmental episodes. Particularly vulnerable ages are from conception to 3 years and during puberty. Thus, ADHD may be a consequence of severe chronic stress that causes dopamine deficiency, which in turn leads to brain developmental dysfunction. Brain development disorder and ADHD Ultimately, the growing brain should not care whether the dopamine that is actually needed for development and is now lacking is reduced because of a genetic basis, an epigenetically inherited ancestral experience, or a stress experience of its own.

The permanent changes in neurotransmitter levels (dopamine, norepinephrine, and others) seen in AD(HHD) may be triggered by inherited gene variants (stress-independent), may be caused by acute environmental influences, or may be the result of environmental influences that trigger epigenetic changes that can then also be passed on (over a limited number of generations). (*⇒ How ADHD develops: genes or genes + environment
In the first years of life, the most important brain regions and neurotransmitter systems develop. A stress-induced disturbance during this development easily leads to permanent maladjustments of the neurotransmitter systems. Depending on the genetic disposition as well as the type and intensity of early childhood stress, the disruption of the maturation of the dopaminergic pathways can be made up for with a time delay.13

9.3. Learning problems due to changes in the dopamine system in ADHD, chronic and acute stress

An increase in phasic dopamine by acute stress increases long-term potentiation (LTP) via D1 receptor-dependent afferents from the hippocampus to the PFC,14 while chronic stress impairs LTP.15. Dopaminergically induced changes in phosphorylation of second messenger molecules such as CREB and DARPP-32 are required for induction of LTP.1617 Their effects last well beyond the period of dopamine receptor stimulation.18
Electrical stimulation in the PFC triggers LTP when tonic dopamine is present. If this is absent, as after several weeks of chronic stress, long-term depression (LTD) is triggered instead.1918

9.4. Alteration of dopamine degradation in ADHD

According to one view, ADHD sufferers have too many DAT in the striatum, which declines with age. A 50-year-old has only half as many dopamine transporters as a 10-year-old.20 This could explain, on the one hand, why ADHD disappears in some sufferers after adolescence and, on the other hand, why symptoms change in adulthood.
DAT occur primarily in the striatum, where they bear the brunt of dopamine degradation.
If there are too many too active DAT in the striatum, the dopamine released by the sending nerve cell into the synaptic cleft to the receiving nerve cell is already reabsorbed there by these overactive reuptake transporters (located on the sending side of the synapse) before it could be taken up by the receptors of the receiving nerve cell. Thus, a deficiency of dopamine occurs. Thus, the signal that should be delivered by the dopamine does not arrive cleanly at the receiving nerve cell.
ADHD drugs, nicotine (smoking - though dysfunctional as a drug) and zinc block the DAT and thus reduce its hyperactivity.21 However, to successfully treat ADHD with zinc, amounts of zinc would have to be taken that are otherwise hazardous to health (zinc flu).

Studies of dopamine levels in ADHD in areas other than the striatum have been highly inconsistent and suffer from small subject numbers.22
One study (with small subject numbers) found slightly decreased dopamine metabolism in the left, medial, and right PFC in ADHD.23 Another study with a very small number of subjects found increased dopamine levels in ADHD in the right midbrain.24
Another study suggests that in ADHD, dopamine is decreased in the PFC, whereas norepinephrine is increased.25

Other studies also suggest underactivation of the PFC and other brain areas outside the striatum. See The neurological explanation of drive and motivation problems, collapsed there at the end of the article.

In chronic stress - depending on the origin and constellation - a tonic dopamine deficiency is given, just as in early and prolonged stress a downregulation is also described with regard to the stress hormones CRH and cortisol and their receptors.26

Although downregulation of CRH and cortisol can be verified by the dexamethasone or combined dexamethasone/CRH test, we have encountered use of this test for ADHD in only a few reports.
Cortisol in ADHD

In ADHD and autism, beta-phenyletlyamine (a dopamine degrader but not a peptide) might be decreased in urine.27

9.5. Alteration of dopamine synthesis in ADHD?

The effect of dopamine deficiency in the PFC and striatum may result from reduced dopamine action by desensitized receptors in addition to reduced dopamine levels. This may result from increased degradation of dopamine (too much(e) or too active DAT, COMT, MAO-A, etc.) or from deficient dopamine synthesis.

Various studies on the question of whether dopamine synthesis is impaired in ADHD did not come to a clear conclusion.28
Two studies found evidence of increased synthesis of phenylalanine (a precursor to dopamine),2930 two studies found evidence of decreased phenylalanine production in ADHD3132 and one study found no differences between ADHD sufferers and non-affected individuals.33

9.6. Dopamine deficiency in the striatum due to overactivated PFC?

9.6.1. DAT elevation in the striatum?

Many results are conflicting as to whether dopamine transporters are increased or decreased in ADHD:

  • Increased DAT in inattention in adolescents with ADHD and cerebral blood flow problems after preterm birth.34
    Increased DAT is associated with decreased tonic and increased phasic dopamine levels, as we understand it.
  • 6 of 8 studies found increased DAT binding in (mostly drug-naïve) children and adults with ADHD-HI. 3 studies found decreased DAT binding after methylphenidate treatment.35
  • The 3′-UTR but not the intron8 VNTR genotype of the DAT gene correlated with increased DAT binding in ADHD-HI affected as in unaffected individuals. S3′-UTR polymorphism of the DAT gene and ADHD-HI status had an additive effect on DAT binding.36
  • One study found evidence more suggestive of decreased DAT number or binding in ADHD.37
  • DAT and D2 and D3 receptors showed reduced binding in ADHD sufferers in38
    • DAT
      • Nucleus accumbens
      • Midbrain*
      • Left caudate nucleus
    • D(2)/D(3) receptors
      • Nucleus accumbens*
      • Midbrain*
      • Nucleus caudatus left*
      • Hypothalamus*
    • Regions marked with * showed a correlation with attention problems
  • Certain gene polymorphisms of the DAT gene appear to contribute to ADHD. Frequently mentioned are 9R and 10R. One study found higher working memory activity at 9R and 10R in different brain regions in ADHD.39
  • Methylation of the dopamine transporter gene in blood may also be an indicator of DAT density in the striatum and may eventually serve as a tool for ADHD diagnosis.40
  • Lack of oxygen at birth increases the risk of ADHD.41 Hypoxy-ischemic conditions around birth (e.g., asphyxia) cause a deficient supply of oxygen to the brain. This can lead to cognitive impairment, and its occurrence after oxygen deficiency is influenced by dopamine transporter gene polymorphisms.42

To our knowledge, studies to date have not differentiated by subtype. The evidence we have gathered on the different (phasic) cortisol stress responses of the subtypes would justify investigating this question taking the subtype into account.

9.6.2. High dopamine level in the mPFC decreases dopamine level in the striatum

Acute severe stress briefly increases dopamine levels in the PFC (dopamine stress response, phasic dopamine).
Chronic stress and early childhood stress can permanently increase or decrease dopamine levels in the PFC (basal dopamine levels, tonic dopamine), depending on the stressor and age at exposure. For more on this, see ⇒ Neurophysiological correlates of stress.

The mPFC controls the interplay between subcortical regions that control pleasure-oriented actions. Increased excitability of the mPFC results in a decreased dopaminergic response of the striatum. This inhibits the drive of behavior to dopaminergic stimulation. Sustained overactivation of the mPFC results in stable suppression of natural reward-motivated behavior (encoded with phaic dopain) and correlates in degree with anhedonic behavior. In summary, much dopamine in the (m)PFC decreases dopamine levels in the nucleus accumbens43 and in the striatum.44454647

This mechanism could be based on the fact that dopamine in the PFC decreases the activity of glutamatergic pyramidal cells and stimulates GABAergic cells, which also inhibits glutamate. This could lead to a strong inhibition of glutamatergic projection in BA 9 and BA 10, triggering a reduction of dopamine levels in the ventral and dorsal striatum.48

Blockade of dopamine receptors in the PFC results in disinhibited dopamine turnover in the striatum.47

According to other sources, anhedonia correlates with decreased dopamine levels in the mesocorticolimbic system and nucleus accumbens.49 The dysfunction of the dopaminergic system in anhedonia is thought to be directly remediable with ketamine medication.50

(Tonic) dopamine deficiency correlates with an increase in dopamine transporter numbers.51

9.7. Decreased tonic and increased phasic dopamine in the caudate nucleus in ADHD

An MRI study found evidence in adults with ADHD-C of decreased tonic dopamine levels at rest and increased phasic dopamine levels during a flanker task, both in the right caudate nucleus (part of the striatum).52

Another study also found evidence of increased phasic dopamine in the striatum and linked this to symptoms of high impulsivity and low inhibition.53

Another model assumes decreased tonic dopamine in the striatum as a cause of ADHD.54


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