10. ADHD - Disorders of the dopamine system

In our opinion, ADHD mediates its symptoms in a similar way to chronic stress through a lack of dopamine and noradrenaline, among other things.

We also believe that chronic stress in early childhood, as well as genetic, epigenetic or other causes of dopamine and noradrenaline deficiency, can impair brain development, leading to ADHD symptoms. See under ⇒ Brain development disorder and ADHD in the chapter Development.

• 10.1. Genetic abnormalities with a dopaminergic background in ADHD
• 10.2. Changes in the dopamine system in ADHD, chronic and acute stress
• 10.3. Learning problems due to changes in the dopamine system in ADHD, chronic and acute stress
• 10.4. In ADHD, striatum underactivated during reward expectation, overactivated during reward retention
• 10.5. Various dopaminergic hypotheses for ADHD
  • 10.5.1. Change in dopamine degradation in ADHD
  • 10.5.2. Changes in dopamine synthesis in ADHD?
  • 10.5.3. Dopamine deficiency in the striatum due to overactivated PFC?
    • 10.5.3.1. DAT increase in the striatum?
    • 10.5.3.2. High dopamine levels in the mPFC reduce dopamine levels in the striatum
  • 10.5.4. Tonic and phasic dopamine in explanatory models for ADHD
    • 10.5.4.1. DA release tonically and phasically reduced: Dynamic Development Theory (DDT)
    • 10.5.4.2. DA release phasically reduced in response to reward anticipation: dopamine transfer deficit theory (DTD; Tripp and Wickens, 2008)
    • 10.5.4.3. Dopamine release tonically reduced, phasically increased: Grace, 1991, 2001
    • 10.5.4.4. ADxS.org hypothesis: dopamine release tonically reduced or increased, phasically impaired
  • 10.5.5. Tonic and phasic dopamine in explanatory models for ASD

10.1. Genetic abnormalities with a dopaminergic background in ADHD¶

In ADHD, a striking number of polymorphisms (specific gene variants) are involved in genes that influence 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 the ADHD-I subtype (without hyperactivity), the PFC is primarily affected.² Given that hyperactivity arises neurophysiologically in the striatum and can be caused there by reduced or excessive dopamine levels, this would be plausible.
• DRD5
• DAT1
  • Dopamine transporters (DAT) bear the main burden of dopamine degradation in the striatum.
• COMT
  • Dopamine degradation in the PFC is primarily carried out by the enzyme COMT and NET, which reabsorb more dopamine in the PFC than noradrenaline. 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 is 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. Val/Met or Met/Met variants, on the other hand, showed significantly poorer sustained attention in children with ADHD than the normal values.⁴ This could also be explained by the fact that ADHD is associated with excess dopamine in the PFC, as increased dopamine depletion would then bring the dopamine level into the mid-range associated with optimal cognitive ability. This is because dopamine excess and dopamine deficiency are equally impairing.⁵. However, this clashes with the fact that amphetamine drugs, 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 degradation) and worsened it in healthy Met/Met gene carriers (slowed dopamine degradation).⁶ However, it is possible that such persons with ADHD could also be AMP nonresponders.
  • Mb-COMT knockout mice (mice without membrane-bound COMT) show increased dopamine levels in the striatum. This indicates that mb-COMT is also involved in dopamine degradation in the striatum.⁷

10.2. Changes in the dopamine system in ADHD, chronic and acute stress¶

The specialist literature assumes that ADHD is characterized by reduced dopamine and noradrenaline levels in the PFC and striatum / nucleus accumbens,⁸ as is also the case with chronic stress. Acute stress, on the other hand, is characterized by increased dopamine levels in these brain regions.⁹¹⁰ The symptoms of dopamine and noradrenaline deficiency (ADHD, chronic stress) and dopamine and noradrenaline excess (acute stress) are nevertheless partly identical and confusable. They occur when the optimal neurotransmitter level for the transmission of information in the brain is exceeded or undercut (inverted-U theory).¹¹⁸ The main people with ADHD 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. Although the DAT-KO mouse shows drastically increased basal dopamine levels in the striatum, the phasic release of dopamine in the striatum is reduced. The DAT-KO mouse (especially the heterozygous variant, in which the DAT is approximately halved) shows almost the full range of ADHD symptoms. There are (rarely) also people without or with very severely reduced DAT. However, these show other symptoms that are not typical of ADHD (e.g. early childhood Parkinson’s dystonia) and are therefore rarely misdiagnosed with ADHD and are more likely to be misdiagnosed with cerebral palsy. Many people with ADHD die as teenagers.¹² An excess of extracellular dopamine leads to reduced production of dopamine (and thus reduced storage of dopamine in the vesicles) through activation of presynaptic D2 autoreceptors, as well as downregulation or desensitization of dopamine receptors, resulting in a lack of phasic dopamine and a dopamine effect deficiency.¹³

While acute and chronic stress in adulthood generally cause reversible neurotransmitter changes, repeated acute stress or chronic stress can cause permanent damage, particularly during phases of brain development. Particularly vulnerable ages are from conception to 3 years and during puberty. For example, ADHD can be a consequence of severe chronic stress that causes a dopamine deficiency, which in turn leads to a brain development disorder. ⇒ Brain development disorder and ADHD Ultimately, the growing brain should not care whether the dopamine that is actually needed for development and is now missing is reduced due to a genetic basis, an epigenetically inherited ancestral experience or a personal experience of stress.

The permanent changes in neurotransmitter levels (dopamine, noradrenaline and others) in ADHD can be triggered by inherited gene variants (stress-independent), caused by acute environmental influences or be the result of environmental influences that trigger epigenetic changes, which can then also be passed on (over a limited number of generations). (⇒ How ADHD develops: genes or genes + environment)
The most important brain regions and neurotransmitter systems develop in the first few years of life. A stress-related disorder during this development can easily lead to permanent maladjustments of the neurotransmitter systems. Depending on genetic disposition and the type and intensity of early childhood stress, the Disorder in the maturation of the dopaminergic pathways can be delayed.¹⁴

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

An increase in phasic dopamine due to acute stress increases long-term potentiation (LTP) via D1 receptor-dependent afferents of the hippocampus in the PFC,¹⁵ while chronic stress impairs LTP.¹⁶ Dopaminergic-induced changes in the phosphorylation of second messenger molecules such as CREB and DARPP-32 are required for the induction of LTP.¹⁷¹⁸ Their effects last far beyond the period of dopamine receptor stimulation.¹⁹
Electrical stimulation in the PFC triggers LTP when tonic dopamine is present. If this is missing, as after several weeks of chronic stress, long-term depression (LTD) is triggered instead.²⁰¹⁹

10.4. In ADHD, striatum underactivated during reward expectation, overactivated during reward retention¶

In adolescents with ADHD, activation of the ventral striatum was reduced during reward anticipation compared to healthy controls. Activation of the ventral striatum correlated negatively with hyperactive/impulsive symptoms.²¹
Reward anticipation correlates with the availability of DAT in the nucleus accumbens.²²
Neuronal activity in the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation correlated with reward-related dopamine release in the ventral striatum, the main target of SN/VTA dopamine neurons. Neuronal activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release.²³

10.5. Various dopaminergic hypotheses for ADHD¶

There are various models to explain how the dopaminergic system is altered in ADHD.²⁴ All of them can explain the behavioral changes in people with ADHD.
We assume that the different models do not contradict each other, but that they can apply - alone or in combination - to different people with ADHD.

Some studies indicate an increased dopamine transporter density with rapid reuptake of synaptic dopamine, leading to a lack of dopamine in the synaptic cleft.²⁵²⁶²⁷
The fact that, according to recent studies, dopaminergic synapses do not contain dopamine receptors but GABA receptors, and that the dopaminergic receptors are instead arranged spatially around the synapse, does not change the significance of the DAT, as they are also located outside the synapse.

Other studies assume a dopamine deficit, together with a low dopamine release, which is associated with a low transporter density in untreated cases.²⁸²⁹

Recent PET imaging studies suggest that transporter density is reduced in drug-naïve persons with ADHD and increases with chronic treatment with stimulants.³⁰³¹

10.5.1. Change in dopamine degradation in ADHD¶

According to one view, people with ADHD have too many DAT in the striatum, which decreases with age. A 50-year-old has only half as many dopamine transporters as a 10-year-old.³² This could partly explain why ADHD disappears in some people with ADHD after adolescence and why the symptoms change in adulthood.
DAT occur predominantly in the striatum, where they bear the main burden of dopamine degradation.
If there are too many overactive DAT in the striatum, the dopamine released by the sending nerve cell into the synaptic cleft to the receiving nerve cell is taken up again by these overactive reuptake transporters (located on the sending side of the synapse) before it can be taken up by the receptors of the receiving nerve cell. This results in a lack of dopamine. As a result, the signal that should be transmitted by the dopamine does not arrive cleanly at the receiving nerve cell.
ADHD medication, nicotine (smoking - although dysfunctional as a drug) and zinc block the DAT and thus reduce its overactivity.³³ However, in order to successfully treat ADHD with zinc, amounts of zinc would have to be taken that are otherwise hazardous to health (zinc flu).

10.5.2. Changes in dopamine synthesis in ADHD?¶

The effect of a dopamine deficiency in the PFC and striatum can result not only from a reduced effect of dopamine through desensitized receptors but also from a reduced dopamine level. This can result from an increased breakdown of dopamine (too much (e) or too active DAT, COMT, MAO-A etc.) or from insufficient dopamine synthesis.

Various studies on the question of whether dopamine synthesis is impaired in ADHD have come to no clear conclusion.⁴⁰
Two studies found evidence of increased synthesis of phenylalanine (a precursor to dopamine),⁴¹⁴² two studies found evidence of reduced phenylalanine production in people with ADHD⁴³⁴⁴ and one study found no differences between people with ADHD and those without.⁴⁵

10.5.3. Dopamine deficiency in the striatum due to overactivated PFC?¶

10.5.3.1. DAT increase in the striatum?¶

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

• Increased DAT for inattention in adolescents with ADHD and cerebral circulation problems after preterm birth.⁴⁶
• 6 of 8 studies found increased DAT retention in (mostly drug-naïve) children and adults with ADHD-HI. 3 studies found reduced DAT binding after methylphenidate treatment.⁴⁷
• The 3′-UTR but not the intron8 VNTR genotype of the DAT gene correlated with increased DAT binding in persons with ADHD-HI as in non-affected individuals. S3′-UTR polymorphism of the DAT gene and ADHD-HI status had an additive effect on DAT binding.⁴⁸
• One study found evidence more suggestive of reduced DAT count or retention in ADHD.⁴⁹
• DAT showed reduced retention in people with ADHD²⁸
  • Nucleus accumbens
    • Medication-naïve adults with ADHD showed statistically significantly lower DAT availability in the bilateral nucleus accumbens. The reduced DAT correlated with increased inattention⁵⁰
  • Midbrain*
  • Caudate nucleus left
• D2 and D3 receptors showed reduced binding in persons with ADHD²⁸
  • Nucleus accumbens*
  • Midbrain*
  • Caudate nucleus on the left*
  • Hypothalamus*
  • The 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.⁵¹
• Methylation of the dopamine transporter gene in the blood could also be an indicator of DAT density in the striatum and one day serve as a tool for ADHD diagnosis.⁵²
• Oxygen deficiency at birth increases the risk of ADHD.⁵³ Hypoxy-ischemic conditions around birth (e.g. asphyxia) cause an inadequate supply of oxygen to the brain. This can lead to cognitive impairments, the occurrence of which is influenced by dopamine transporter gene polymorphisms after oxygen deprivation.⁵⁴

Most studies do not differentiate between ADHD subtypes. 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.

10.5.3.2. High dopamine levels in the mPFC reduce dopamine levels in the striatum¶

Acute severe stress increases the dopamine level in the PFC in the short term (dopamine stress response, phasic dopamine).
Chronic 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. More on this under ⇒ Neurophysiological correlates of stress.

The mPFC controls the interaction between subcortical regions that control pleasure-oriented actions. Increased excitability of the mPFC causes a reduced dopaminergic response of the striatum. This inhibits the drive of behavior to dopaminergic stimulation. Sustained overactivation of the mPFC leads to a stable suppression of natural reward-motivated behavior (encoded with phasic dopamine) and correlates in degree with anhedonic behavior. In summary, high levels of dopamine in the (m)PFC reduce dopamine levels in the nucleus accumbens⁵⁵ and in the striatum as a whole.^56575859

This mechanism could be based on the fact that dopamine in the PFC reduces 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, which triggers a reduction of dopamine levels in the ventral and dorsal striatum.⁶⁰

Conversely, blocking dopamine receptors in the PFC leads to disinhibited dopamine turnover in the striatum.⁵⁹

According to other sources, anhedonia correlates with reduced dopamine levels in the mesocorticolimbic system and in the nucleus accumbens.⁶¹ The dysfunction of the dopaminergic system in anhedonia is said to be directly remediable with ketamine medication.⁶²

(Tonic) dopamine deficiency correlates with an increase in the number of dopamine transporters.⁶³

10.5.4. Tonic and phasic dopamine in explanatory models for ADHD¶

Interestingly, mouse models in which the dopamine receptors were deactivated barely show ADHD symptoms, further emphasizing the importance of the DAT of D2 autoreceptors and its influence on extracellular and phasic dopamine. More on this at ADHD in animal models In the chapter Neurological aspects.

10.5.4.1. DA release tonically and phasically reduced: Dynamic Development Theory (DDT)¶

According to the Dynamic Development Theory (DDT), ADHD has a hypo-dopaminergic cause:

• Reduced tonic firing rate impairs extinction of previously reinforced behaviors⁶⁴
• Flattened phasic dopamine bursts impair reinforcement learning⁶⁴⁶⁵

In silicio, a neuronal basal ganglia model of decreased tonic and phasic dopamine
⁶⁶⁶⁷⁶⁸

• correctly:
  • the go and no-go paths in the striatum
  • the average response time
• do not reproduce correctly
  • the increased reaction time variability that is common in ADHD.

10.5.4.2. DA release phasically reduced in response to reward anticipation: dopamine transfer deficit theory (DTD; Tripp and Wickens, 2008)¶

The dopamine transfer deficit (DTD) theory explains ADHD by means of an attenuated phasic dopamine response to cues (predictors) of expected rewards, resulting in altered reinforcement sensitivity.⁶⁹⁷⁰
If healthy people repeatedly receive a reward at the same time as a predictor, the dopamine neurons begin to fire at the predictor and the reward. If the relationship between reward and predictor is clear (learned), dopamine only fires to the predictor.
In ADHD, the firing of dopamine cells is abnormal. Even when reward and predictor appeared together long enough to have been learned, people with ADHD still show too low a firing rate after the cue and an increased firing rate after the actual reward.
Less efficient learning in ADHD is also associated with a delayed response to an immediate reward. Weaker conditioning to the reward leads to faster extinction of the behavior and a weaker effect of the reinforcer on the behavior over longer periods of time. The lack of anticipatory dopamine signaling of the cue causes faster behavioral extinction when reinforcement is delayed or interrupted. This would explain some core symptoms of ADHD, including the devaluation of delayed rewards.⁷¹

10.5.4.3. Dopamine release tonically reduced, phasically increased: Grace, 1991, 2001¶

Grace’s model assumes decreased tonic dopamine in the striatum as a cause of ADHD.⁷²
Another study also found evidence of increased phasic dopamine in the striatum and linked this to symptoms of high impulsivity and low inhibition.⁷³ An MRI study in adults with ADHD-C found evidence of reduced tonic dopamine levels at rest and increased phasic dopamine levels during a flanker task, both in the right caudate nucleus (part of the striatum)⁷⁴
ADHD showed increased striatal BOLD (= phasic) responses to reward expectancy and reward payoff.
During reward anticipation in ADHD, the BOLD response observed in controls was absent in the right ventral and left dorsal striatum (negatively correlated to hyperactivity/impulsivity symptoms), while during the response to reward in ADHD, the BOLD response was increased in the ventral striatum bilaterally and in the left dorsal striatum (positively correlated to hyperactivity/impulsivity symptoms).⁷⁵

A decrease in tonic dopamine activity correlates with an increase in phasic bursts⁷⁶. This imbalance is the result of impaired presynaptic regulation of dopamine at the terminal level, not the consequence of centrally reduced tonic dopamine activity, as is suspected in chronic stress⁷⁷⁷⁸ An abnormally low tonic extracellular dopamine level in ADHD leads to an upregulation of autoreceptors, so that stimulus-induced phasic dopamine is increased.⁷⁹
This results in excessive reward reinforcement. Consequences of this

• Impulsiveness⁸⁰
• Preference for smaller immediate rewards over larger delayed rewards⁸¹

Véronneau-Veilleux et al showed in a computer model that this theory also reflects the increased reaction time variance.⁸²

A measurement of tonic and phasic dopamine release in ADHD subjects using dynamic molecular imaging technique during performance of the Eriksen-Flanker task (phasic) or at rest (tonic) showed in the right caudate nucleus:⁸³

• reduced tonic release
  • significantly higher ligand binding potential at rest
• increased phasic release
  • significantly lower ligand binding potential during the flanker task

In other parts of the striatum, this distribution tended to be similar, but not significant. This supports the hypothesis of overactive DAT.

A PET study also found evidence of a phasic hyperdopaminergic state in ADHD⁸⁴

This is countered by the fact that a rare DAT gene variant was found in two male siblings with ADHD (A559V), which showed:⁸⁵

• tripled dopamine efflux, with depolarized cell potentials
  • at the level triggered by AMP in normal DAT
• MPH and AMP both blocked Ala559Val-mediated dopamine efflux
  • in wild-type HDAT, MPH and AMP increased this
• increased sensitivity to intracellular Na+, but not to intracellular dopamine
• possibly increased basal hDAT A559V phosphorylation, which is attenuated by AMP
• normal DAT protein and cell surface expression
• normal dopamine (re)uptake at both low and high dopamine levels
• normal effect of AMP, MPH, cocaine on dopamine reuptake inhibition
• an older A559V carrier showed
  • high hyperactivity/restlessness
  • high impulsivity/emotional susceptibility
  • high hyperactive-impulsive symptom scores according to DSM-IV (over 90)

The DAT gene variant 12P572A also shows an increased DAT efflux with less dependence on ion or dopamine concentrations.⁸⁶

In our opinion, the increased efflux is likely to indicate increased extracellular dopamine levels in persons with ADHD, as is also the case with ASA.

One indication against excessive phasic dopamine in ADHD could be that AMP, even at a drug dose of 1 mg/kg (albeit injected), increased not only extracellular but also phasic dopamine.⁸⁷

One indication of excessive phasic dopamine in ADHD is the increased tendency to eat high-fat fast food in ADHD.

ADHD is not a consequence of unhealthy food intake, but unhealthy food intake is a consequence of ADHD.⁸⁸ People with ADHD are more likely to choose unhealthy foods,⁸⁹ with a “junk food” pattern of sweetened beverages and desserts and the “Western” dietary pattern of red meat, refined grains, processed meat and hydrogenated fat correlated with an increased likelihood of ADHD-HI by up to 37%.⁹⁰

A high-fat Western diet attenuated phasic dopamine release and attenuated the dopaminergic response to DAT inhibition.⁹¹ A diet high in saturated (not: unsaturated) fats reduced phasic dopamine release, slowed dopamine uptake in the nucleus accumbens⁹² and attenuated D1 signaling.⁹³
If unhealthy, high-fat diets are a consequence of ADHD, this could indicate that people with ADHD find a reduction in phasic dopamine pleasurable.
However, a high-fat diet also reduced DAT-DA reuptake,⁹⁴ which has an increasing effect on extracellular dopamine.

10.5.4.4. ADxS.org hypothesis: dopamine release tonically reduced or increased, phasically impaired¶

According to our current understanding, an excess as well as a deficiency of extracellular dopamine should be associated with ADHD symptoms.

The above-mentioned specialist and research literature assumes a reduced extracellular dopamine level in ADHD due to a reduced tonic dopamine output (see above).
Overactive DAT (or D2 autoreceptors) cause reduced extracellular dopamine levels. Although the vesicles that feed the phasic release of dopamine are well filled by highly active DAT, overactive DAT take up the phasically released dopamine before it can transmit its signal to the receptors. Above all, however, a reduced extracellular dopamine level leads to inadequate inhibition of phasic dopamine and thus to ADHD symptoms.

However, this alone is difficult to reconcile with the high comorbidity between ADHD and ASD, as ASD is associated with an excess of extracellular dopamine. See under Autism - another Disorder of the Dopamine System
It should be considered certain that excessive extracellular dopamine levels (due to insufficient DAT reuptake and/or excessive DAT efflux) cause ASD symptoms such as rigidity and repetitive behaviors.
It should also be considered certain that important areas of ADHD symptoms (movement, motivation and, as a consequence of motivation, attention) are primarily controlled by phasic dopamine. However, our previous explanatory model would be compatible with this if not only a reduced but also an excessive tonic dopamine level led to problems with phasic dopamine activity.

Underactive DAT and thus excessive extracellular dopamine levels are understood to have several adverse effects on phasic dopamine signaling:
First, an excess of dopamine in the extracellular space as noise is likely to interfere with phasic signaling.
Second, the dopaminergic vesicles are unlikely to be adequately refilled by the underactive DAT, so phasic dopamine release relies solely on newly synthesized dopamine, which cannot supply them on its own.
Therefore, according to our understanding, extracellular hyperdopaminergic as well as hypodopaminergic states should impair signal transmission by phasic dopamine.

A hint in this direction can be found in the presentation by Gatzke-Kopp et al (2007), according to which a high tonic dopaminergic input (and possibly a high DAT efflux) leads to a high extracellular dopamine level, which downregulates the phasic dopamine responses triggered by stimuli via D2 autoreceptors. Tonic dopamine mediates the regulatory (inhibitory) control of the PFC on the ventral striatum, thus inhibiting the (phasic) activity of the striatum. In response to reward stimuli, the striatum fires phasically in a dopaminergic manner and activates dopaminergic postsynaptic receptors. Tonic control is therefore inhibitory and modulates excitatory phasic firing in response to reward stimuli.⁹⁵
According to another account, the extracellular “background” dopamine level caused by tonic firing does not appear to trigger D2 autoreceptor feedback depression. It is possible that the level is too low to stimulate the low-affinity D2 receptors.⁹⁶

Since phasic dopamine can only be released by neurons that are previously tonically active (see Dopamine release (tonic, phasic) and coding), this would be a possible explanatory model:

ASS alone:

• high extracellular dopamine (ASA symptoms) due to high efflux, not due to high tonic activity
  • More on this at Autism - another Disorder of the Dopamine System
• normal phasic dopamine (no ADHD symptoms) due to non-increased tonic activity or due to downregulation by high extracellular dopamine
  • (like Gatzke-Kopp et al, 2007)

ADHD alone:

• low tonic, high phasic (like Grace, see above)
  • low extracellular dopamine due to overcompensation of high tonic activity by overactive DAT (like Grace, see above)
  • high phasic dopamine due to lack of downregulation, as low extracellular dopamine
• low tonic, low phasic (like Dynamic Development Theory, DDT see above)
  • increased reaction time variability may occur more frequently in ADHD compared to non-affected people and thus characterize ADHD as a disorder. However, the results of the ADxS.org reaction test only showed increased reaction time variability in less than half of people with ADHD, so it is not a sufficiently defining characteristic.

ASD and ADHD comorbid

• high extracellular dopamine (ASA symptoms) due to high efflux and simultaneously high tonic activity
• high phasic dopamine due to high tonic activity
  • but why is there no downregulation of phasic dopamine by high extracellular dopamine?
    Conceivable if downregulation requires high tonic dopamine and high extracellular dopamine is not sufficient for downregulation.

In contrast, the hyperdopaminergic state in schizophrenia is thought to be caused by a massive loss of inhibitory parvalbumin-expressing GABA-ergic interneurons in the limbic hippocampus, resulting in dopaminergic overactivity of the anterior (rodents: ventral) hippocampus, resulting in excessive tonic dopamine firing and a hyper-responsive dopamine system underlying the positive symptoms of schizophrenia.⁹⁷

10.5.5. Tonic and phasic dopamine in explanatory models for ASD¶

Various animal models and research on DAT1 gene variants indicate an increased tonic dopamine level in ASD (due to increased dopamine efflux or minimized dopamine reuptake). More on this under Autism - another Disorder of the Dopamine System
This raises the question of how the frequent comorbidity between ADHD and ASD can be reconciled with this dichotomy. According to our hypothesis, it is conceivable that ASD derives its ADHD symptoms from an excess of extracellular dopamine, as is the case in the DAT-KO mouse animal model, for example, while ADHD without ASD derives its symptoms from a lack of extracellular dopamine, as is the case in SHR.
In ASD, noradrenaline also appears to be increased extracellularly. One study replicated other studies showing that children with ASD have increased tonic (resting pupil diameter) and decreased phasic (PDR and ERP) activity of the locus coreuleus-noradrenaline system. The tonic and phasic LC-NE indices correlated primarily with ADHD symptoms and not with ASD symptomatology.⁹⁸