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Extracellular dopamine in the synaptic cleft can be degraded by reuptake into dopaminergic neurons or, after uptake into glial cells, by MAO or COMT. Within dopaminergic neurons, dopamine located outside vesicles is degraded by MAO.1 Further, dopamine can be deactivated by sulfation or glucuronidation as well as by metabolism to norepinephrine.
7.1.1. Dopamine reuptake by dopamine transporter (DAT)¶
The DAT is a plasma membrane transport protein responsible for regulating the duration and intensity of dopaminergic signaling. Altered function of the DAT has been implicated in ADHD and ASD. DAT are subject to epigenetic changes in expression within the first months of life due to environmental influences. The dopamine transporter (DAT) transports not only dopamine but also norepinephrine.2
DAT1 is located on chromosome 5p15.3. DAT occurs in several variants that are distinguished by the number of 40-bp repeats (allele repeats), which range from 3 to 11 repeats (R). The 10R variant with 480 bp is most frequent with 70% and the 9R variant with 440 bp with 27% in the Caucasian and Hispanic population and with 72% and 17% in the African population, which showed much more frequent rare allele repeat variants with 12%.34
Dopamine reuptake is dependent on sodium.5 If sodium is removed from the extracellular space, DAT cannot reuptake dopamine. The sodium gradient is the driving force of dopamine transport in the nucleus accumbens.6
Sodium substitution causes rapid hyperpolarization of the membrane, which decreases dopamine efflux.7 Decreased DAT activity may play a role in producing increased NAc-DA transmission during appetite for Na (salt: NaCl), which may underlie the motivational properties of sodium in the sodium-depleted rat.
While DAT 10R causes increased dopamine removal from the synaptic cleft, thus decreased tonic (but unaffected or even increased phasic dopamine), DAT 9R causes decreased dopamine removal, thus increased tonic and decreased phasic dopamine. DAT 10R is associated with ADHD, DAT 9R with borderline.
DAT regulate the temporal availability of dopamine (and to a lesser extent norepinephrine) in the synaptic cleft or presynaptic neuron,9 by rapidly removing released dopamine from the synapse. This fine-tunes the phasic nature of the dopamine signal,10 because only when the synaptic cleft is quickly cleared of ejected dopamine is phasically ejected (signal-encoding) dopamine able to cleanly transmit these signals unaffected by tonic dopamine. For the distinction between tonic and phasic dopamine, see ⇒ above 1.2. tonic dopamine / phasic dopamine.
DAT cause most dopamine degradation in the striatum. In the PFC, on the other hand, fewer DAT are present - there, dopamine degradation takes place primarily via COMT (60%) and only slightly via DAT (15%).11 In the PFC, noradrenaline transporters (NET) significantly reabsorb dopamine.
Norepinephrine 17,000 Km
Smaller values mean a higher binding affinity.
Whereas in the striatum COMT dopamine degradation appears to be by membrane-bound COMT (mb-COMT), in the PFC only fluid COMT appears to be involved. Mb-COMT knockout mice (mice lacking membrane-bound COMT) show increased dopamine levels in the striatum but not in the PFC. This suggests that mb-COMT is involved in dopamine degradation in the striatum, whereas only fluid COMT may be involved in the PFC.13
In addition to removing dopamine from the synaptic cleft in the striatum, the DAT modulates the signal-to-noise ratio of dopamine neurotransmission and affects presynaptic dopamine levels.14
If 60 to 70% of the dopamine transporters are blocked by cocaine, this increases the level of dopamine in the synaptic cleft and at the same time reduces acetylcholine release. A subjective feeling of elation results (due to the very rapid and high rise in dopamine, unlike drugs). Cocaine as well as anticholinergics cause a subjective calming in the affected persons as well as a reduction of motor restlessness and extrapyramidal symptoms due to the reduction of acetylcholinergic release. At the same time, especially in the case of cocaine, psychotic symptoms are exacerbated by the dopamine excess induced by dopamine transporter blockade.15
DAT - at least in the substantia nigra - can also regulate dopamine release. While the D2 dopamine autoreceptor downregulates dopamine when extracellular dopamine is high, the DAT promotes dopamine release when dopamine is low. Unlike methylphenidate, which inhibits dopamine reuptake by DAT, amphetamine is a substrate for DAT that may trigger dopamine release in the substantia nigra.1612
126.96.36.199. Up- and downregulation of the dopamine transporter¶
DAT are also regulated by extracellular dopamine levels. A decrease in dopamine synthesis decreased the density of DAT and its function in the striatum, and an increase in dopamine levels caused an upregulation of DAT binding.17 Stimulation of D2 autoreceptors also resulted in downregulation of DAT in the striatum.18 This suggests a compensatory downregulation or upregulation of DAT, as an adaptation to reduced or increased dopamine levels, respectively. Downregulation of DAT has also been observed in midbrain dopaminergic cells after loss of dopamine synapses in the striatum.19
Alpha-methyl-p-tyrosine also causes downregulation of DAT in the striatum20
188.8.131.52. Dopamine transporter increased or decreased in ADHD?¶
While the question of which DAT gene variant is more common in ADHD is regularly answered with “DAT 10R”, statements about whether DAT numbers tend to be increased or decreased in ADHD are contradictory.
However, the consequences seem to be partly identical.
Decreased DAT number/DAT activity results in increased extracellular dopamine levels (tonic hyperdopaminergic) and decreased phasic release due to deficiently refilled vesicles, whereas increased DAT number/DAT activity results in decreased extracellular dopamine levels (tonic hyperdopaminergic), with concomitant excessive reuptake of phasically released dopamine, preventing its action at receptors. However, both hypotheses conclusively explain a decreased phasic dopaminewirklevel (phasic hypodopaminergic).
184.108.40.206.1. Hypothesis 1: reduced DAT number in ADHD (consequence: extracellular hyperdopaminergic, phasic hypodopaminergic)¶
A meta-analysis of 9 studies concluded that medication-naïve ADHD sufferers had a 14% reduction in the number of DAT in the striatum, whereas previously medicated ADHD sufferers had an increased number of DAT compared with unaffected individuals.21 The study, meanwhile, appears to have limitations regarding the issue of defining medication naïveté.22
A recent study also found a correlation between more inactive DAT and ADHD, while an increased active DAT correlated with alcohol addiction.23
220.127.116.11.2. Hypothesis 2: increased DAT number in ADHD (consequence: extracellular and phasic hypodopaminergic)¶
Other sources report that in adults with ADHD, the number of dopamine transporters in the striatum is increased by 70% compared to non-affected individuals.24
A possible conclusion could be that increased DAT levels in ADHD lead to a decrease in synaptic and extra-synaptic = extracellular dopamine. It is also conceivable that an increase in DAT is an adaptive upregulation response to compensate for an increased level of dopamine release.
In both cases, methylphenidate can normalize these levels.25
18.104.22.168.4. PEA affects DAT via TAAR1 and D2 autoreceptors (?)¶
PEA (beta-phenylethylamine)26 and dopamine27 affect DAT (Slc6A3) function via both TAAR1 and D2 autoreceptors. Another study found no effect on DAT in TAAR1-KO mice or by TAAR1 agonists or TAAR1 antagonists in wild-type mice.28
7.1.2. Dopamine reuptake by norepinephrine transporter (NET)¶
The norepinephrine transporter (NET) is common in the PFC and rare in the striatum, whereas the DAT is rare in the PFC and common in the striatum. The NET is slightly more affine to dopamine than to norepinephrine,2930 so that a relevant part of dopamine degradation/reuptake in the PFC (but not in the striatum) occurs through the NET.
The norepinephrine transporter appears to be reduced in ADHD in the right hemisphere attentional networks.31
Norepinephrine 539 / 580 Km
Smaller values mean a higher binding affinity.
NET-KO mice (mice lacking noradrenaline transporter) do not show effective dopamine degradation in PFC32
In the DAT-KO mouse, NET in the striatum was shown to possibly contribute little to dopamine degradation in the striatum. Inhibition of serotonin transporters, norepinephrine transporters, MAOA, or COMT did not alter dopamine degradation in the striatum of the DAT-KO mouse. This appears to occur more by diffusion in the absence of DAT in the striatum.33 We wonder, however, whether the process by which DAT is deactivated in the DAT-KO mouse might not also deactivate NET, since the latter also takes up dopamine.
7.1.3. Dopamine reuptake by plasma membrane monoamine transporter (PMAT)¶
Dopamine and norepinephrine are further taken up by the plasma membrane monoamine transporter (PMAT) in addition to the DAT and NET. This is also called human equilibrative nucleoside transporter-4 (hENT4). It is encoded by the gene SLC29A4. Its binding affinity is lower than that of DAT or NET. It binds high-affinity dopamine and serotonin and, much more weakly, norepinephrine, epinephrine, and histamine.34
7.1.4. Dopamine reuptake by organic cation transporters (OCT)¶
Dopamine (although weaker than norepinephrine) continues to be taken up from the extracellular area to a lesser extent by the organic cation transporters (OCT1, OCT2, OCT3). These are also referred to as solute carrier family 22 member 1/2/3 or extraneuronal monoamine transporters (EMT). OTC2 and OTC3 are found in neurons and astrocytes and bind histamine > norepinephrine and epinephrine > dopamine > serotonin.34 Uptake does not occur in the presynaptic cell as in DAT and NET, but in glial cells. There, dopamine and norepinephrine are degraded by COMT to methoxytyramine.35
Dopamine reuptake inhibitors are substances that inhibit the dopamine transporter (DAT). The term thus refers to the inhibited transporter and not to the inhibition of neurotransmitter reuptake. Dopamine reuptake inhibitors are
Norepinephrine reuptake inhibitors are substances that inhibit the norepinephrine transporter (NET). The name is therefore based on the inhibited transporter and not on the inhibition of neurotransmitter reuptake. Norepinephrine reuptake inhibitors include.
While dopamine transporters cause the reuptake of dopamine from the synaptic cleft back into the transmitting cell, where it is reincorporated into vesicles by VMAT2 transporters, dopamine is also degraded by conversion into other substances. COMT and MAO are the main ones to be mentioned here.
COMT metabolizes predominantly catecholamines, thus also dopamine, by O-methylation. S-adenosyl-L-methionine (SAM) acts as the methyl donor.
22.214.171.124. Dopamine degradation in PFC by NET and COMT, hardly by DAT; in striatum by DAT, hardly by NET and COMT¶
No COMT is found in nigrostriatal neurons.1
In the striatum, therefore, dopamine is hardly degraded by COMT. Instead, many DAT are found in the striatum.37383940
The PFC has comparatively few dopamine transporters (DAT), unlike the striatum.37383940
Therefore, the PFC needs other pathways to degrade dopamine (which is increased in the PFC during stress). For this purpose, in addition to NETs, it makes particular use of the enzyme catechol-O-methyltransferase (COMT), which deactivates dopamine by adding a methyl group and which causes 60% of dopamine degradation in the PFC (and only 15% of dopamine degradation in the striatum). The other important dopamine degradation enzyme is monoamine oxidase B (MAO-B).41424344
However, COMT is found predominantly in glial cells, especially microglia, and hardly or not at all in neurons.45 Apparently, dopamine from the synaptic cleft is also taken up in glial cells.1
In addition to dopamine, COMT also metabolizes levodopa and thus inhibits dopamine synthesis. COMT inhibitors such as entacapone, tolcapone and opicapone are used in the treatment of Parkinson’s disease.46
COMT is controlled by the COMT gene. COMT gene polymorphisms that influence the activity of the COMT gene therefore primarily affect the dopamine level of the PFC and hardly affect the dopamine level in other brain regions.
126.96.36.199. COMT isoforms: soluble and membrane-bound¶
metabolizes mainly dopaminergic and noradrenergic catecholamines
Whereas in the striatum COMT dopamine degradation appears to be by membrane-bound COMT, in the PFC only soluble COMT might be involved. Mb-COMT knockout mice (mice lacking membrane-bound COMT) show increased dopamine levels in the striatum but not in the PFC. This suggests that Mb-COMT is involved in dopamine degradation in the striatum, whereas only soluble COMT may be involved in the PFC.13
188.8.131.52. COMT gene variants alter dopamine levels in the PFC¶
The homozygous Val158Val polymorphism of the COMT gene causes 4 times faster dopamine degradation than the homozygous COMT-Met158Met variant, which causes a more inactive COMT and thus slower dopamine degradation.4748 The Val158Met polymorphism lies between the rapidly degrading Val158Val and the slowly degrading Met158Met with respect to catecholamine metabolism.
Healthy COMT-Met158Met carriers are
Vs. COMT-Val158Val carriers (probably due to the higher dopamine level in the PFC)
Mentally more powerful (more efficient, not more intelligent)49
More task switching problems, less mental flexibility
Carriers of at least one Met allele showed greater task switching costs (i.e., lower cognitive flexibility) than carriers of the homozygous Val/Val COMT gene. This suggests that low prefrontal dopamine levels correlate with higher cognitive flexibility and lower task switching problems.50
More stress sensitive
High dopamine level (only) in the PFC already at rest
Significant increase in dopamine (only) in the PFC even during mild stress
In addition, they have a lower susceptibility to psychosis and schizophrenia with cannabis abuse.54 This is plausible in that schizophrenia is associated with increased dopamine levels in the striatum,55 and increased dopamine levels in the PFC reduce dopamine levels in the striatum.56
Social impairments are significantly increased,51 whereas this study found no direct influences of the COMT gene on ADHD.
Carriers of at least one Val allele, which represents strong dopamine depletion, showed significantly higher cooperativeness and altruism than Met/Met carriers in one study.61
Healthy Val/Val subjects have suboptimally low dopamine levels, whereas Met/Met subjects have near-optimal dopamine levels in the baseline state.62 Val/Val subjects achieve optimal dopamine levels by reduced COMT activity or by increased dopamine turnover in the PFC (e.g., acute stress), whereas these changes have the opposite effect in Met/Met subjects.63
The association of mental performance and high sensitivity via the COMT-Met158Met polymorphism may be an element that could explain the correlation between giftedness and high sensitivity.64
COMT-Met158Met is an opportunity-risk gene along with DRD 4 7R and 5HTTPR. Opportunity-risk gene determine performance and vulnerability in our view. ⇒ How ADHD develops: genes + environment
COMT Val/Val and DAT 10R in combination correlated with increased hyperactivity and increased ADHD symptoms at 18 years in 11- to 15-year-old boys, but not in girls.65 This is explained by the fact that COMT VAL/VAL degrades dopamine in the PFC particularly rapidly and DAT 10R represents strong dopamine reuptake from the synaptic cleft in the striatum, both of which lead to low dopamine effects typically assumed in ADHD.
This correlates with the fact that in ADHD, sufferers with COMT Val/Val respond better to stimulants (which increase dopamine levels in the PFC) than sufferers with COMT Met/Met.66
Surprisingly, another study found improved sustained attention in children with ADHD who carried the Val/Val variant. Children with ADHD and the Val/Met or the Met/Met variant showed significantly worse sustained attention than the norm values.67 This would be more conclusive if ADHD were associated with dópaminergic hyperfunction in the PFC, since increased dopamine depletion would then bring dopamine levels into the midrange associated with optimal cognitive ability. This is because dopamine excess and dopamine deficiency are equally impairing.68 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).69
Carriers of the COMT Val/Val polymorphism, which synthesizes more COMT in the PFC, which degrades dopamine faster, thus leading to lower dopamine levels in the PFC, may have lower tonic and increased phasic dopamine levels in subcortical brain regions.70 However, this hypothesis is not without controversy.57
One study found significantly lower connectivity of the right crus I/II with the left dlPFC in Met carriers than in Val/Val carriers.71
COMT-Met158Met causes low dopamine levels in the PFC and high dopamine levels in the striatum.
In the PFC, dopamine is degraded by COMT, which deactivates dopamine by adding a methyl group. COMT causes about 60% of dopamine degradation in the PFC and only 15% of dopamine degradation in the striatum.72424344
Mice with COMT excess due to the COMT Met158Val gene variant showed decreased dopamine levels in the PFC. At the same time, the dopamine level in the striatum was also increased in them.73
COMT and Borderline
Borderline correlates genetically significantly to the COMT Met158Met polymorphism, which is further amplified when the COMT Met158Met and 5-HTTPR-short alley gene polymorphisms coincide.74
That the coincidence of several genes that increase or decrease (here: increase) a neurotransmitter (here: dopamine) in the same brain region (here: PFC) increases sensitivity and vulnerability is plausible. That the five times slower degradation of dopamine in the PFC due to COMT Met158Met compared to COMT Val158Val basically leads to an increased mental performance as well as to an increased susceptibility to stress could confirm the hypothesis of Andrea Brackmann, who noticed a strikingly large number of at least partially highly gifted people among her borderline patients.75
Further considerations for COMT
The following considerations are purely hypothetical and not yet verified:
COMT may explain a relevant difference between ADHD and Parkinson’s disease, both characterized by dopamine deficiency. In Parkinson’s disease, COMT inhibitors prove to be helpful. Dopamine is also decreased in the PFC in ADHD.
The breakdown of dopamine and norepinephrine by COMT requires S-adenosyl-L-methionine (SAM) and a metal, usually magnesium.76 This could explain why magnesium deficiency can trigger ADHD symptoms.
Similarly, in a small study of 8 ADHD sufferers, SAM was able to reduce ADHD symptoms in 6 of them (all MPH responders).77
Insofar as the degradation of dopamine by COMT affects tonic dopamine, we believe it w#re conclusive that this improves the signal-to-noise ratio of phasic dopamine.
TNF-alpha, a proinflammatory cytokine, downregulates COMT mRNA and protein in certain cells. NF-κB, the target of TNF-alpha and an important regulator of inflammation, binds to COMT and inhibits its expression in the CNS.78
Attenuated COMT activity simultaneously decreases glucose tolerance in mice.
COMT produces the estrogen 2-methoxyestradiol (2-ME), which is relevant for glucose tolerance. Reduced COMT activity therefore leads to reduced glucose tolerance via reduced 2-ME production.79
184.108.40.206.1. Estrogen decreases COMT and thus dopamine degradation by COMT in the PFC¶
Estrogen decreases COMT transcription. Depending on the COMT gene variant, this causes varying degrees of sex-related and menstruation-dependent changes in the dopamine level of the PFC.37
COMT inhibitors (which increase dopamine levels) therefore improve (in the presence of excess dopamine in the PFC) primarily the executive abilities of the PFC, but not the symptoms of hyperactivity or impulsivity laid down in the striatum.8081
The PFC already reacts to small reductions in availability of the dopamine precursor tyrosine with a significant decrease in dopamine, unlike other brain areas, e.g. the striatum, which remains unaffected.82 However, this is only relevant in phenylketonuria (PKU) and not in ADHD.
Since estrogen is a female sex hormone, women should more often have excessive dopamine levels in the PFC.
220.127.116.11.2. Hypoxia, vascular occlusion, and traumatic brain injury increase COMT¶
Hypoxia, blood vessel occlusion, and traumatic brain injury increase the expression of COMT in hippocampal microglia. This appears to be a compensatory mechanism to terminate excessive catecholamine signaling in injured brain regions.83
Just as COMT promotes dopamine degradation in the PFC and estrogen can inhibit dopamine degradation by reducing COMT, other COMT inhibitors should also inhibit dopamine degradation in the PFC.
Taking these drugs could therefore be helpful in ADHD - if a dopamine deficiency in the PFC is actually triggered by COMT overactivity.
A genetic test can show which COMT polymorphism is present. This may indicate whether corresponding symptoms of impaired working memory result from a dopamine excess or a dopamine deficiency in the PFC.
However, since other genes have an influence on the dopamine level of the PFC, a test result is only one of several factors. Therefore, a combination with testing of other gene candidates that also have an influence on the dopamine level of the PFC, e.g. the DAT gene or the 5 dopamine receptors, might be indicated.
This knowledge may provide a clue as to whether nonresponding to stimulants could possibly result from increased levels of dopamine or norepinephrine in the PFC.
A COMT gene test is offered for around €60 (as of 2019). We do not know whether testing several genes together is cheaper.
7.2.2. Dopamine degradation by monoamine oxidase (MAO-A, MAO-B)¶
Dopamine is degraded by both isoenzymes of MAO, MAO-A and MAO-B. In humans, the degradation by MAO-A predominates in vivo (within the degradation by MAO), because hardly any dopamine reaches astrocytes, where it could be degraded by MAO-B.
in vitro in the cortex 70% by MAO-B, 30% by MAO-A89
but: there is hardly any DAT in astrocytes, so little dopamine enters them in vivo, where it could be degraded by MAO-B86
on the other hand: Astrocytes (like microglia) can synthesize and metabolize dopamine themselves.91 Astrocytes and microglia are in direct contact with dopaminergic neurons. It is possible that glial cells participate in the maintenance of dopamine levels in the brain in both healthy and pathological states. However, astrocytes are unable to convert L-DOPA they ingest into dopamine.
In people with Parkinson’s disease, MAO-B is upregulated in the brain
thereby excessive DA degradation, which contributes to the development of Parkinson’s disease
irreversible MAO-B inhibitors (selegiline, rasagiline) are effective in Parkinson’s disease (to a limited extent)
mAO-B inhibition also prevents the formation and transmission of α-synuclein aggregates92
Oxidative deamination of catecholamines by MAO produces hydrogen peroxide. Hydrogen peroxide generates oxidative stress in catecholaminergic or catecholamine-degrading cells.
All catecholamines - including dopamine - are susceptible to oxidation at their electron-rich catechol moiety. Besides MAO, enzymatic oxidation can further be caused by
Cyclooxygenases (COX, prostaglandin H synthase)
With oxygen as the electron acceptor, these reactions generate superoxide radical anions (OO-⋅2).
Enzymatic oxidation of dopamine or L-dopa, spontaneously or by metal catalysis (Fe 3+), produces highly reactive electron-deficient orthoquinones (DOPA-quinone and dopamine-quinone). DOPA-quinone and dopamine-quinone react readily with nucleophiles. Quinones, as well as ROS, can react nonspecifically with many cellular components and alter their functionality, which is potentially neurodegenerative.
Salsolinol85 Salsolinol is an alkaloid and tetrahydroisoquinoline.
Chocolate (cocoa) contains significant amounts of the alkaloids salsonisole (up to 2.5 mg) (1-methyl-6,7-dihydroxy-tetrahydroisoquinoline) and salsoline (1-methyl-6,-methoxy-7-hydroxy-tetrahydroisoquinoline).95
18.104.22.168. Sulfation deactivates dopamine to dopamine sulfate¶
Sulfation of dopamine causes a breakdown of active dopamine to inactive dopamine sulfate.
Sulfation of dopamine as well as other catecholamines and bioamines serves to modulate and transport them.
It is much more pronounced and important in humans than in rodents.96 Sulfoconjugation is the major form of dopamine inactivation in human serum, whereas glucuronidation predominates in rats. Thus, no ortholog of SULT1A3 is known in rodents97
Human plasma dopamine sulfate is derived primarily from the sulfoconjugation of dopamine synthesized in the gastrointestinal tract from L-DOPA. Both dietary and endogenous factors affect plasma dopamine sulfate. There appears to be an enzymatic gut-blood barrier to detoxify exogenous dopamine and limit the autocrine/paracrine effects of endogenous dopamine formed in a “third catecholamine system.”98
Serum dopamine sulfate levels (approximately 5 ng/ml) are 10 to 15 times higher than levels of free dopamine (0.3 ng/ml), norepinephrine (0.2 ng/ml), or epinephrine (0.05 ng/ml). Dopamine sulfate is not detectable by routine analytical methods and requires special extraction procedures.99 After first meal following fasting, serum dopamine sulfate levels increase 50-fold. Food intake appears to stimulate peripheral dopamine synthesis and/or dopamine sulfoconjugation in the gastrointestinal tract.99
The sulfation reaction is catalyzed by sulfotransferases (SULT). Sulfation plays an important role in the homeostasis and regulation of catecholamines, steroids, and iodothyronines, as well as in the detoxification of xenobiotics. There are two SULT enzyme superfamilies:99
SULT1 (phenol sulfotransferases or PST)
consists of 6 homodimeric enzymes
has high specificity for both catecholamines and catecholestrogens 
A single amino acid substitution (Glu 146) gives the enzyme a higher affinity for DA than for NE or Epi .
high mirror in
moderate mirror in
SULT2 (steroid sulfotransferases)
SULT are found in a wide variety of human tissues:
PST appears to be an important regulator of dopamine storage and metabolism.
L-dopa altered PST in Parkinson’s disease patients99
greatly reduced in
weakly reduced in
unchanged in the
Meynert nucleus (nucleus basalis)
doubled in the
22.214.171.124. Sulfatases reactivate dopamine sulfate to dopamine¶
Sulfoconjugation is reversible by sulfatases (unlike glucuronidation; this is irreversible).101
Sulfatases convert the biologically inactive dopamine sulfate into a non-conjugated, active dopamine.
To date, 17 sulfatases are known in humans. These are predominantly located in the lysosome.
Arylsulfatase A (ARSA)
Arylsulfatase B (ARSB)
Arylsulfatase C (estrone/dehydroepiandrosterone sulfatase; steroid sulfatase, STS)
Arylsulfatase C (STS) is associated with inattention, cognition problems, and other ADHD symptoms.102103104105
Arylsulfatase C (STS, steroid sulfatase) cleaves sulfate groups from steroid hormones, which alters their biological activity. This also affects dehydroepiandrosterone sulfate (DHEAS).
Sulfated and nonsulfated steroids can affect GABA-A and NMDA receptors in the brain.106 Both DHEAS and its non-sulfated form DHEA inhibit the GABA-A receptor and activate the NMDA receptor.107
More about DHEA at DHEA in the chapter Neurological aspects / Hormones in ADHD.
7.2.4. Glucuronidation by glucuronosyltransferases¶
UDP-glucuronosyltransferases (UGTs) are involved in the detoxification of xenobiotics. They thus contribute to the protection of the organism against hazardous chemicals. Detoxification takes place in the liver. Humans have 19 UGT isoforms, which are divided into three subfamilies: UGT1A, UGT2A and UGT2B.
In the brain, UGTs are mainly expressed in endothelial cells and astrocytes of the blood-brain barrier, but are also found in brain regions lacking a blood-brain barrier, such as the circumventricle, pineal gland, pituitary gland, and neuro-olfactory tissue.108 In addition to their key role as detoxification barriers, UGTs are also involved in maintaining the balance of endogenous compounds such as steroids or DA. In humans, only the UGT isoform UGT1A10 is able to catalyze the glucuronidation of dopamine to a significant extent. Dopamine-4-O-glucuronide as well as dopamine-3-O-glucuronide are formed. However, UGT1A10 is not found in the brain in humans, only isoforms 1A, 2A, 2B, and 3A. Therefore, according to current knowledge, UGTs are not involved in dopamine metabolism in the human brain.109
7.2.5. Dopamine degradation by dopamine-β-hydroxylase (DBH) to norepinephrine¶
Dopamine-β-hydroxylase is a copper-dependent mono-oxygenase that converts dopamine to norepinephrine.
DBH polymorphisms are associated with:110
Dopamine and norepinephrine levels are altered in disorders of copper metabolism. Infants with Menkes Disease, which is caused by an ATP7A gene defect, exhibit marked copper deficiency in the brain. The impaired CNS copper supply is associated with higher dopamine and lower norepinephrine levels in the brain and plasma in these patients, which is used in the clinical diagnosis of the disease. The change in catecholamine levels is thought to be caused by the loss of copper incorporation into dopamine-β-hydroxylase and thus its decreased activity. Restoration of ATP7A expression in the mouse model of Menkes disease corrects the dopamine-norepinephrine ratio, especially when accompanied by additional copper injections.111
However, ATP7A has not yet been identified as a gene candidate for ADHD.
Salsolinol inhibits dopamine-β-hydroxylase.85
Bleomycin is a potent inhibitor of dopamine-β-hydroxylase.112
In the DAT-KO mouse, inhibition of serotonin transporters, norepinephrine transporters, MAO-A, or COMT did not alter dopamine degradation in the striatum. This appears to occur more by diffusion in the absence of DAT in the striatum.33
7.4.1. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT¶
The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes inhibition of the activity of the respective transporters.12
The norepinephrine transporter - along with COMT - is responsible for most dopamine degradation in the PFC, whereas the DAT regulates it significantly in the striatum.
Binding affinity: stronger with smaller number (KD = Ki)
34 - 200
d-AMP (Elvanse, Attentin)
34 - 41
23.3 - 38.9
3,830 - 11,000
1451 - 1600
2.6 - 5
48 - 77
7.4.2. Effect of MPH, AMP, ATX on dopamine / norepinephrine per brain region¶
The drugs methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) alter extracellular dopamine (DA) and norepinephrine (NE) differently in different brain regions. Table based on Madras,12 modified.
DA + NE (+)
DA + NE +/- 0
DA + NE +/- 0
DA + NE +
DA + NE +/- 0
DA + NE +/- 0
DA + NE +
DA +/- 0 NE +/- 0
DA +/- 0 NE +/- 0
Note: The NET binds DA more strongly than NE (only in the PFC), the DAT binds DA much more strongly than NE.
[Han, Rowell, Carr (1999): D2 autoreceptors are not involved in the down-regulation of the striatal dopamine transporter caused by alpha-methyl-p-tyrosine. Res Commun Mol Pathol Pharmacol. 1999;104(3):331-8. PMID: 10741383.)](https://pubmed.ncbi.nlm.nih.gov/10741383/ ↥