Dear reader of, please excuse the disruption. needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find useful, please take a minute and support with your donation. Thank you!

Since 01.06.2021 is supported by the non-profit ADxS e.V..

$21963 of $63500 - as of 2024-05-31
Header Image
8. Dopamine reuptake, dopamine degradation


8. Dopamine reuptake, dopamine degradation

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 of vesicles is degraded by MAO.1 Furthermore, dopamine can be deactivated by sulfation or glucuronidation and converted into noradrenaline by metabolism. Finally, dopamine can diffuse and is then transported away with the blood.

8.1. Dopamine reuptake (recycling)

Transporters are divided into high-affinity transporters with low transport capacity (uptake-1 transporters: DAT, NET, SERT) and low-affinity transporters with high transport capacity (uptake-2 transporters: PMAT, OCT). Uptake-1 transporters are located on presynaptic cells and cause reuptake of the neurotransmitter for reuse for release or efflux. Uptake 2 transporters are located on glial cells, which degrade the neurotransmitter. All transporters are located outside the synaptic cleft2
In SERT-KO mice, OCT3 (and possibly other uptake-2 transporters) are upregulated to compensate for serotonin degradation.2 Conversely, they could impair the effect of SSRIs.

8.1.1. Dopamine reuptake through dopamine transporters (DAT)

The DAT (also known as DAT1) is a plasma membrane transport protein that is responsible for regulating the duration and intensity of dopaminergic signal transmission. The function of the DAT is often altered in ADHD and ASD.

DAT (re)absorb dopamine from the extracellular space and transport it into the cell. This can be dopamine that has been released by the cell itself (reuptake) or dopamine that comes from neighboring cells.
DAT are located near the synapses. With the reuptake, the DAT regulate the temporal availability of primarily phasic and less tonic3 freshly released dopamine (and to a lesser extent noradrenaline) in the synaptic cleft or in the presynaptic nerve cell.4 This ensures fine-tuning of the phasic nature of the dopamine signal,5 because only when the synaptic cleft is quickly cleared of previously released dopamine is newly released (signal-encoding) dopamine able to transmit these signals cleanly, unimpaired by dopamine present from previous releases. By removing dopamine from the synaptic cleft, the DAT modulates the signal-to-noise ratio of dopamine signaling.6
For a distinction between tonic and phasic dopamine, see Dopamine release (tonic, phasic) and coding.
The tonic extrasynaptic dopamine level is less affected by the reuptake3

DAT cause most of the dopamine degradation in the striatum. In contrast, fewer DAT are present in the PFC, where dopamine degradation is mainly carried out by COMT (60 %) and NET and only slightly via DAT (15 %).7 In the PFC, noradrenaline transporters (NET) significantly reabsorb dopamine.
There are 5 times as many DAT in the nucleus accumbens as in the basolateral amygdala.8

The binding affinity of DAT is for:9

  • Dopamine 885 / 2140 / 5,200 Km
  • Noradrenaline 17,000 Km
    Lower values mean a higher affinity for commitment.

DAT are subject to epigenetic changes in expression within the first few months of life due to environmental influences. In addition to dopamine, the dopamine transporter (DAT) also transports noradrenaline.10 In addition, the DAT can transport neurotoxic compounds such as 6-hydroxydopamine, 1-methyl-4-phenylpyridinium or environmental chemicals such as paraquat, which makes it a gateway for harmful substances and a possible mechanism for dopaminergic neurodegeneration in Parkinson’s disease.11

The DAT is located on chromosome 5p15.3 and occurs in different variants that differ in the number of 40 bp repeats (allele repeats), which range from 3 to 11 repeats (R). The most common are the 10R variant with 480 bp 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 significantly more rare allele repeat variants with 12 %.1213
While DAT 10R causes increased dopamine degradation from the synaptic cleft, resulting in decreased tonic (but unaffected or even increased phasic dopamine), DAT 9R causes decreased dopamine degradation, resulting in increased tonic and decreased phasic dopamine. DAT 10R is associated with ADHD, DAT 9R with borderline.

DAT are expressed within a dopaminergic neuron:14

  • in the terminal area
  • along the axon
  • around the soma and the dendrites (somatodendritic area)
  • predominantly perisynaptic (at the edge of the synapse) in the intracellular membranes of dopaminergic cells
  • on the outer plasma membranes of small distal dendrites

DAT are dynamically regulated by a variety of cellular factors.
Their expression in different brain regions or within a specific cell is not static, but very plastic.

  • A deletion of the first 22 amino acids of DAT15
    • Strongly reduces AMP-induced dopamine efflux
    • (Re)admission remains unchanged
    • Eliminates 32P incorporation in DAT in response to PKC activation16
  • Mutation of the five N-terminal serines to alanine15
    • Causes a strong reduction in AMP-induced dopamine efflux
    • (Re)admission remains unchanged
  • Mutation of the five N-terminal serines to aspartate (mimicry of phosphorylation)15
    • Efflux remains intact
    • Phosphorylation of one or more of these five N-terminal serines is probably required for AMP-induced dopamine efflux

While COMT dopamine degradation in the striatum appears to be mediated by membrane-bound COMT (mb-COMT), only liquid COMT appears to be involved in the PFC. Mb-COMT knockout mice (mice without 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, while only liquid COMT may be involved in the PFC.17

If 60 to 70 % of the dopamine transporters are blocked by cocaine, this increases the dopamine level in the synaptic cleft and at the same time reduces the release of acetylcholine. The result is a subjective feeling of elation (due to the very rapid and high increase in dopamine, unlike with drugs). Both cocaine and anticholinergics have a subjective calming effect on those affected as well as a reduction in motor restlessness and extrapyramidal symptoms due to the reduction in acetylcholinergic release. At the same time, especially with cocaine, the excess dopamine induced by the dopamine transporter blockade intensifies psychotic symptoms.18

8.1.2. Further dopaminergic influences of the DAT Dopamine release (efflux) through DAT

DAT can also release dopamine - at least in the substantia nigra. While the D2 dopamine autoreceptor downregulates the release of dopamine when extracellular dopamine is high, the DAT promotes the release of dopamine when dopamine is low. Unlike methylphenidate, which inhibits dopamine reuptake by the DAT, amphetamine is a substrate for the DAT that may trigger dopamine release in the substantia nigra.199 According to another account, MPH also increases DAT efflux (see under MPH).
Only the increase in population activity by inhibiting GABAergic afferents from the pallidum (but not the activation of pedunculopontine inputs, which increases burst firing) increases dopamine efflux in the ventral striatum. However, after blockade of dopamine reuptake, increased burst firing increased dopamine efflux three times more than increased population activity3

AMP and the drug METH also stimulate efflux through DAT,20 while MPH does not. Channel function of the DAT

DAT not only transport dopamine, but also appear to have a channel mode that directly modulates membrane potential and neuronal function.
The depolarizing currents caused by DAT thus result not only from the high density and fast neurotransmitter turnover rate of a classical transporter, but also from a genuine channel behavior of DAT.21

8.1.3. Dopamine reuptake by noradrenaline transporters (NET)

The noradrenaline transporter (NET) is common in the PFC and rare in the striatum, while the DAT is rare in the PFC and common in the striatum. The NET is slightly more affine to dopamine than to noradrenaline,2223 so that a relevant part of dopamine degradation / dopamine reuptake in the PFC (but not in the striatum) is carried out by the NET.
The noradrenaline transporter appears to be reduced in the attention networks of the right hemisphere of the brain in ADHD.24

The binding affinity of NET is for:9

  • Dopamine 240 / 730 Km
  • Noradrenaline 539 / 580 Km
    Lower values mean a higher affinity for commitment.

NET-KO mice (mice without noradrenaline transporter) show no effective dopamine degradation in the PFC25

In the DAT-KO mouse, it was shown that NET in the striatum may hardly contribute to dopamine degradation in the striatum. Inhibition of serotonin transporters, noradrenaline transporters, MAOA or COMT did not alter dopamine degradation in the striatum of the DAT-KO mouse. In the absence of DAT in the striatum, this appears to occur more by diffusion.26 However, we wonder whether the process by which the DAT is deactivated in the DAT-KO mouse could also deactivate the NET, since the NET also takes up dopamine.

8.1.4. Substances that inhibit the reuptake of dopamine (reuptake inhibitors) Dopamine reuptake inhibitors

Dopamine reuptake inhibitors are substances that inhibit the dopamine transporter (DAT). The term therefore refers to the inhibited transporter and not the inhibition of neurotransmitter reuptake.
Dopamine reuptake inhibitors are (in bold: typical ADHD medications)

  • Amineptin
  • Amphetamines
  • Bupropion
  • Bromantane
  • CE-15827
  • Dasotraline
  • Difemetorex
  • Difluoropin
  • Fencamfamine
  • Lefetamine
  • Levophacetoperane
  • Medifoxamine
  • Mesocarb
  • Methyl naphthidate (HDMP-28)28
  • Methylphenidate
  • Nomifensin (trade names: Alival, Merital, Psyton)
  • Pipradrol
  • Prolintan
  • Pyrovalerone
  • Reserpine
  • Solriamfetol
  • Vanoxerin (in development) Noradrenaline reuptake inhibitors

Noradrenaline reuptake inhibitors are substances that inhibit the noradrenaline transporter (NET). The term is therefore based on the inhibited transporter and not on the inhibition of neurotransmitter reuptake.
Selective noradrenaline reuptake inhibitors (SNRIs) include

For ADHD treatment:

  • Atomoxetine (Strattera®, Atomoxe®, Agakalin®, Atomoxetine generics)
  • Viloxazine
    For the treatment of depression:
  • Reboxetine (Solvex®, Edronax®)
  • Viloxazine (Vivalan®; approval was no longer extended by the manufacturer, preparation therefore no longer available)

For obesity treatment:

  • Mazindol

As a skeletal muscle relaxant:

  • Orphenadrine (Norflex®)


  • Nisoxetine (never approved)

8.2. Dopamine degradation

8.2.1. Dopamine degradation through uptake-2 transporters Dopamine degradation by plasma membrane monoamine transporter (PMAT)

PMAT and OCT are so-called uptake-2 transporters, as they have a low affinity (Kd = 252 compared to 0.27 μM) with a transport capacity that is around 80 times higher than uptake-1 transporters such as DAT, NET or SERT (Vmax = 100 nmol/min/g tissue compared to 1.22 nmol/min/g tissue). They work independently of sodium and bidirectionally.29 However, uptake-2 transporters are not only active at very high substrate concentrations, but at any substrate concentration.30
Since uptake 2 transporters are hardly ever located on (dopamine-releasing) dopamine neurons, but primarily on (dopamine-degrading) glial cells, PMAT and OCT 1 to 3 are not used for reuptake, but for dopamine degradation.

In addition to the DAT and NET, dopamine and noradrenaline are taken up by the plasma membrane monoamine transporter (PMAT). This is also known as 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 dopamine and serotonin and, to a much lesser extent, noradrenaline, adrenaline and histamine.31

The32 PMAT, discovered in 2004, is widespread in the human brain.33 PMAT is found

  • widely distributed in the brain2
  • Amygdala2
  • Cerebral cortex2
  • Hippocampus2
  • Striatum2
  • on the CSF side of the endothelial cells of the blood-CFS barrier in the choroid plexus34
    • Choroid plexuses are tangle-like arteriovenous vascular bundles made up of specialized glial cells. They are found in the ventricles of the brain and are responsible for the production of cerebrospinal fluid, the formation of the blood-cerebrospinal fluid barrier and the resorption and detoxification of cerebrospinal fluid.35

PMAT-KO mice are viable, fertile and show normal physiological characteristics.2

PMAT gene polymorphisms with reduced transport activity for the monoamines serotonin and dopamine as well as the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) correlate with autism spectrum disorders (ASD).36
PMAT-KO mice (which therefore have a PMAT deficiency) show neither a strong change in brain histamine levels nor behavioral abnormalities outside of stressful situations.3433

PMAT gene variants with reduced activity are thought to be involved in ASD.2 Dopamine degradation by organic cation transporters (OCT)

Like PMAT, OCT are so-called uptake-2 transporters. See above.

Dopamine (although weaker than noradrenaline) is transported from the extracellular area not only by the uptake transporters DAT and NET, but also, albeit to a lesser extent, by the organic cation transporters (in rats: OCT1, OCT2, OCT3; in humans: only OCT237 Uptake does not take place in the presynaptic cell as with DAT and NET, but in glial cells. There, dopamine and noradrenaline are degraded by COMT to methoxytyramine.38

The coding genes are:39

  • OCT1: SLC22A1
  • OCT2: SLC22A2
  • OCT3: SLC22A3

Strong OCT antagonists are e.g.38

  • Amantadine
  • Memantine OCT1


  • relatively low expression in the brain40
  • is found in astrocytes in the brain, but not in neurons.
  • OCT1-KO mice are viable, fertile and show normal physiological characteristics41

OCT1 (SLC22A1) transports with low affinity but relatively high turnover

  • endogenous monoamines such as
    • N-1-methylnicotinamide (NMN)
    • Guanidine
    • Histamine
  • Neurotransmitters such as
    • Dopamine
    • Serotonin
    • Adrenalin
    • Acetylcholine
  • Is involved in
    • hepatic absorption of vitamin B1/thiamine
    • Intake of xenobiotics OCT2

Like OCT3, OCT2 reuptakes histamine, but has not been found in human astrocytes,42 but in the human brain, as do OCT1 (SLC22A1), OCTN1 (SLC22AN1) and OCTN2 (SLC22AN2).43


  • is widespread in the brain, e.g. in
    • limbic regions (e.g. amygdala)
    • Cerebral cortex
    • Hippocampus
    • Striatum
  • OCT2 is found in neurons and glial cells (astrocytes, microglia)
  • OCT2-KO mice
    • are viable, fertile and show normal physiological characteristics41
    • reduced anxiety behavior44
    • reduced symptoms of depression (reduced immobile time in the forced swim test and in the tail suspension test)44
    • 1.9-fold stress hormone level (corticosterone)45
    • increased susceptibility to depression due to recurring unpredictable stress45

OCT2 is transported:43

  • similar affinity as OCT1
    • MPP
    • TEA
    • Quinine
    • Metformin
  • 4 times as affine as OCT1
    • Acetylcholine
  • and further
    • Choline
    • Agmatine
  • Neurotransmitters
    • Dopamine
    • Noradrenaline
    • Adrenalin
    • Serotonin
    • Histamine
  • Glutamate receptor antagonists
    • Amantadine
    • Memantine
  • Histamine H2 receptor antagonists
    • Cimetidine
    • Famotidine
    • Ranitidine
  • Cytostatic drug
    • Cisplatin
  • Antihypertensives
    • Debrisoquine

OCT2 is involved in46

  • Memory
  • Pain perception
  • Stress processing:45
    • OCT2 is expressed in various stress-related circuits in the brain and along the HPA axis
    • OCT2-KO mice show
      • increased the hormonal response to acute stress
      • impaired HPA function
      • unchanged sensitivity of the adrenal glands to ACTH
      • much more sensitive reaction to unpredictable chronic mild stress. Changes in:
        • depressive symptoms
        • Self-care
        • spatial memory
        • social interaction
        • stress-sensitive spontaneous behavior
      • Glycogen synthase kinase-3β (GSK3β) signaling pathway altered in the hippocampus
        • GSK3β signaling pathway responds strongly to acute stress in healthy mice
        • in OCT2-KO mice, increased serotonin tone appears to primarily interfere with GSK3β signaling in the brain OCT3

OCT3 shows a low affinity but high capacity for the neurotransmitters noradrenaline, adrenaline, dopamine, serotonin and histamine.4748

OCT3 is the most common OCT in the brain. OCT3 is found in the rodent brain in particular in 4933

  • dopaminergic neurons of the substantia nigra compacta
  • non-aminergic neurons of
    • VTA
    • Substantia nigra reticulata
    • Locus coeruleus
    • Hippocampus
    • Cerebellum
    • Cortex
      • Nucleus accumbens8
      • basolateral amygdala8
        • about the same frequency as in the nucleus accumbens
  • mainly in neurons
  • in astrocytes
    • occasionally in astrocytes in substantia nigra reticulata, hippocampus and several hypothalamic nuclei49
    • in high numbers in astrocytes adjacent to both the soma and the terminals of dopaminergic midbrain neurons5042

OCT3 is primarily found as an autoreceptor on histaminergic neurons, i.e. it inhibits histamine synthesis and histamine release.46
Under normal conditions, OCT3 does not appear to affect brain histamine levels. In OCT3-KO mice, cortex histamine levels were increased after cerebral ischemia, indicating a contribution of the OCT3 transporter to histamine concentration in the brain.33

Although all “uptake-2” transporters are inhibited by corticosterone, they differ in their sensitivity to corticosterone depending on the species and tissue preparation.4351

  • 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 stress-induced glucocorticoid elevation in a rapid, non-genomic manner.48
The deactivation of OCT152 and OCT347 by corticosterone occurs

  • fast
  • through direct interaction of corticosterone with the transporter at specific sites
  • but probably not via glucocorticoid receptors53

We are considering whether this mechanism could explain why ADHD sufferers are able to overcome their otherwise existing procrastination when under high stress and why their motivation is (only) then sufficient to get things done that are not intrinsically interesting. It would at least be conceivable, but so far it is purely hypothetical.

OCT3 remains unaffected by cocaine or antidepressants (desipramine).47

OCT3 inhibitors that are effective in physiological concentrations are:54

  • Azlocillin
  • Aztreonam
  • Famotidine
  • Flufenamic acid
  • Meropenem
  • Propafenone
  • Quinine
  • Trazodone
  • Trimethoprim OCT and ADHD

Methylphenidate binds selectively to OCT1 (IC50: 0.36) and neither to OCT2, OCT3 or PMAT. Ketamine, on the other hand, only binds to OCT255 and PMAT.2
d-Amphetamine is a highly effective hOCT2 reuptake inhibitor (Ki: 10.5 mM) and moderately effective hOCT1 reuptake inhibitor (Ki: 202 mM), while it only interacted with hOCT3 from 100 μM (Ki: 460 mM) (hOCT: human OCT) 5556
d-Amphetamine binds approximately equally strongly to hOCT2 and hOCT3 and to these by an order of magnitude (factor 10) weaker than to DAT56

Binding of amphetamine to OCT may contribute to cellular and behavioral effects of amphetamine.56

OCT3 were found in brain regions relevant for ADHD:

  • in the striatum56
  • Nucleus accumbens8
  • Cerebellum33

OCT2 was found at 56

  • in the hippocampus
    • involved in dopamine-dependent reward-related behavior and responses to amphetamines
  • hardly in dopaminergic systems

OCT3-30%-KO mice showed 5758

  • unchanged spontaneous movement activity
  • increased locomotor activity by methamphetamine compared to METH in wild-type mice
  • increased motor activation to imipramine
  • this could indicate a contribution of OCT3 to noradrenaline and serotonin reuptake
  • Anxiety
    • increased in OCT3-30%-KO mice49
    • reduced in OCT3-100%-KO mice59
  • increased stress values49
  • increased sensitivity to psychostimulants49

With regard to noradrenaline reuptake inhibitors, it has already been hypothesized that drugs that block uptake 2 transporters, such as normetanephrine2, in combination with NET reuptake inhibitors could accelerate the onset of therapeutic benefit in depression.60 Preclinical studies support this hypothesis.2 For example, even much lower doses of venlaflaxine or reboxetine have an antidepressant effect in OCT2-KO mice than in wild-type mice.44 OCT2 reuptake inhibitors also have an antidepressant effect.61
We believe it is worth considering whether this approach could also support the effect of dopamine reuptake inhibitors in ADHD.
These correlations could also explain why MPH, which only binds to OCT1, has less of an antidepressant effect than amphetamine drugs, which inhibit OCT2.

At the same time, in our opinion, it is striking that ADHD medications almost universally cause an increase in histamine, while OCT2 and OCT3 also have a significantly higher affinity for histamine than for noradrenaline and dopamine. An abundant supply of histamine should primarily bind OCT2 and OCT3, thereby reducing the uptake of dopamine and noradrenaline by OCT2 and OCT3 and, as a result, increasing extracellular noradrenaline and dopamine. According to this mechanism, histamine would serve as a dopamine uptake inhibitor.

8.2.2. Dopamine degradation through autooxidation

Dopamine is unstable and can be oxidized by enzymes or metal ions or, in the absence of enzymes or metal ions, auto-oxidize.

The oxidation of DA can produce:

  • low molecular weight ROS62
    • can trigger oxidative stress in dopamine neurons through reversible oxidative modification of macromolecules such as proteins, lipids and nucleic acids
  • 3,4-Dihydroxyphenylacetaldehyde (DOPAL)63
  • highly reactive DA quinones (DAQ)62
    • can induce the susceptibility of dopamine neurons via several toxic mechanisms:
      • irreversible and covalent conjugation with cysteine residues of proteins
        • leads to protein misfolding, inactivation and aggregation
      • free DAQ and DAQ-conjugated proteins can undergo redox cycles and generate harmful ROS
      • endogenous DAQ can cause irreversible inhibition of the ubiquitin-proteasome system
      • DOQ can
        • are converted back to dopamine by reducing agents from the environment
        • are further oxidized to form reactive aminochrome (a type of cyclized DAQ)
          • Aminochrome is more stable than DOQ and can be detected, monitored and characterized
          • DOQ and AM can react and conjugate with many biomolecules, including the protein residues cysteine and tyrosine with sulfhydryl and hydroxyl groups
          • AM is polymerized to neuromelanin (an insoluble granular pigment in the substantia nigra)
            • Neuromelanin
              • prevents the neurotoxicity of DAQs
              • has an antioxidant effect
                • binds and inactivates radical species (ROS) under normal conditions
              • also generates ROS under oxidative stress conditions
                • could thus be involved in the α-syn-associated damage of dopamine neurons

Enzymes (such as tyrosinase) or metal ions (such as iron species or Mn3+) can mediate the oxidation of dopamine in solutions.
Reducing agents, especially glutathione, can effectively prevent auto-oxidation.

Highly reactive DAQ appears to play a more important pathological role than low molecular weight ROS in the degeneration of dopamine neurons in Parkinson’s disease. 62

8.2.3. Dopamine degradation through metabolization (by means of enzymes)

While dopamine transporters cause the reuptake of dopamine from the synaptic cleft back into the sending cell, where it is stored in vesicles again by VMAT2 transporters, dopamine is also broken down by conversion into other substances. COMT and MAO are the most important of these.

Metabolization is the biochemical conversion / breakdown of a substance by the body’s own enzyme systems into a chemically altered metabolite.64

Dopamine degradation occurs with the involvement of the mitochondria and leads to the formation of reactive oxygen species (ROS)65
Under physiological conditions, DA oxidation proceeds slowly so that the cellular antioxidant machinery can cope with the amount of highly reactive products from DA oxidation. Higher dopamine levels lead to increased dopamine oxidation and are toxic to the mitochondria of neurons and glial cells.66 Mitochondrial defects impair dopamine degradation and can lead to increased dopamine levels in the cytosol.67 This interaction between dopamine and mitochondria is involved in the pathogenesis of Parkinson’s disease and schizophrenia.68 Dopamine degradation through COMT

The enzyme COMT mainly metabolizes catecholamines (adrenaline, noradrenaline, dopamine) by O-methylation. S-adenosyl-L-methionine (SAM) acts as a methyl donor.
COMT breaks down dopamine in receiving nerve endings, while MAO is active in receiving nerve endings.Rostain (2015): The Neurobiology of ADHD, Perelman School of Medicine, University of Pennsylvania 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, dopamine is therefore hardly degraded by COMT. However, there are many DAT in the striatum.69707172
The PFC has comparatively few dopamine transporters (DAT), unlike the striatum.69707172

The PFC therefore needs other ways to break down dopamine (which is increased in the PFC under stress). In addition to NETs, it uses 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).73747576

However, COMT is predominantly found in glial cells, especially in microglia, and hardly or not at all in nerve cells.77 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.78

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 have little influence on the dopamine level in other brain regions. COMT isoforms: soluble and membrane-bound

There are two isoforms of COMT:1

  • Soluble COMT (free COMT)
    • freely mobile cytoplasmic form
    • in glial cells
    • in the periphery
    • metabolizes rather exogenous catecholamines
  • Mb-COMT (Membrane-bound)
    • membrane-bound isoform
    • predominant on the neuron membrane
    • higher catecholamine affinity
    • metabolizes mainly dopaminergic and noradrenergic catecholamines

While COMT dopamine degradation in the striatum appears to be mediated by membrane-bound COMT, only soluble COMT may be involved in the PFC. Mb-COMT knockout mice (mice without 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, while only soluble COMT may be involved in the PFC.17 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.7980 The Val158Met polymorphism lies between the rapidly degrading Val158Val and the slowly degrading Met158Met with regard to catecholamine metabolization.
Healthy COMT-Met158Met carriers are

  • Compared to COMT-Val158Val carriers (probably due to the higher dopamine level in the PFC)
    • Mentally more powerful (more efficient, not more intelligent)81
    • 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.82
    • More sensitive to stress
      • High dopamine level (only) in the PFC even at rest
      • Significant increase in dopamine (only) in the PFC even under mild stress
    • More anxious8183
    • Increased loss aversion83 (comparable to the altered behavior in ADHD in relation to punishment) and
    • More sensitive to pain.848580
    • In addition, they have a lower susceptibility to psychosis and schizophrenia with cannabis abuse.86 This is plausible insofar as schizophrenia is associated with an increased dopamine level in the striatum,87 and increased dopamine levels in the PFC reduce the dopamine level in the striatum.88
    • Social impairments are significantly increased,83 although this study did not find any direct influences of the COMT gene on ADHD.
    • Faster response times compared to Val/Val89
    • Müller90 assigns Met158Met to a phenotype, although the source cited by Müller91 does not comment on this:
      • Physique
        • Slim to lean
      • Food intake
        • Can consume large quantities without weight problems
        • In women up to the unjustified suspicion of anorexia nervosa
      • Performance capacity
        • Physical
          • Above average
        • Spiritual
          • Above average
          • Good ability to understand and deal with complex issues
        • High endurance
      • Restlessness
        • Agility to restlessness, hectic, restlessness
        • Inability to recover
          • Yoga, contemplation, meditation are aversive
          • Should also not be expected therapeutically
        • Relaxation through physical activity
      • Anxiety and panic more common
      • Increased aggressiveness
      • Bad losers
      • Differential diagnosis
        • Hyperthyroidism can cause similar symptoms
  • Compared to COMT-Val158Met carriers
    • Less emotionality92
    • Lower extraversion92
    • Lower novelty seeking92
    • Less cooperativeness, less altruism
      • In a study, carriers of at least one Val allele, which stands for a strong dopamine degradation, showed significantly higher cooperativeness and higher altruism than Met/Met carriers.93

Healthy Val/Val carriers have suboptimally low dopamine levels, while Met/Met carriers have almost optimal dopamine levels in the baseline state.94 Val/Val carriers achieve optimal dopamine levels due to reduced COMT activity or increased dopamine turnover in the PFC (e.g. acute stress), whereas these changes have the opposite effect in Met/Met carriers.95

The link between intellectual performance and high sensitivity via the COMT-Met158Met polymorphism could be an element that could explain the correlation between giftedness and high sensitivity.96
COMT-Met158Met is an opportunity-risk gene alongside DRD 4 7R and 5HTTPR. In our opinion, risk-reward genes determine performance and vulnerability.
How ADHD develops: genes + environment

COMT Val/Val and DAT 10R in combination correlated with increased hyperactivity and increased ADHD symptoms at age 18 in 11 to 15-year-old boys, but not in girls.97 This can be explained by the fact that COMT VAL/VAL degrades dopamine in the PFC particularly quickly and DAT 10R stands for strong dopamine reuptake from the synaptic cleft in the striatum, both of which lead to low dopamine effects, as is typically assumed in ADHD.
This correlates with the fact that ADHD sufferers with COMT Val/Val respond better to stimulants (which increase the dopamine level in the PFC) than sufferers with COMT Met/Met.98

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 Met/Met variant showed significantly poorer sustained attention than the norm.99 This would be more conclusive if ADHD were associated with dópaminergic hyperfunction 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.100 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).101

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.102 However, this hypothesis is not uncontroversial.89
One study found significantly lower connectivity of the right Crus I/II with the left dlPFC in Met carriers than in Val/Val carriers.103

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.104747576 Mice with an excess of COMT due to the COMT Met158Val gene variant showed a reduced dopamine level in the PFC and an increased dopamine level in the striatum.105

COMT and Borderline

Borderline correlates genetically significantly with the COMT Met158Met polymorphism, which is further enhanced when the COMT Met158Met and 5-HTTPR-short alley gene polymorphisms coincide.106
It is plausible that the coincidence of several genes that increase or decrease (here: increase) a messenger substance (here: dopamine) in the same brain region (here: PFC) increases sensitivity and vulnerability. The fact that the five times slower dopamine degradation in the PFC due to COMT Met158Met compared to COMT Val158Val generally leads to increased mental performance and increased susceptibility to stress could confirm the hypothesis of Andrea Brackmann, who noticed a conspicuous number of at least partially gifted people among her borderline patients.107

Further considerations for COMT

The following considerations are purely hypothetical and have not yet been verified:
COMT could explain a relevant difference between ADHD and Parkinson’s disease, both of which are characterized by dopamine deficiency. COMT inhibitors have been shown to be helpful in Parkinson’s disease.
Dopamine is also reduced in the PFC in ADHD.

The breakdown of dopamine and noradrenaline by COMT requires S-adenosyl-L-methionine (SAM) and a metal, usually magnesium.108 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).109

Since the degradation of dopamine by COMT affects extracellular dopamine, we think it would be 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.110

Attenuated COMT activity also reduces glucose tolerance in mice.
COMT produces the oestrogen 2-methoxyestradiol (2-ME), which is relevant for glucose tolerance. Reduced COMT activity therefore leads to reduced glucose tolerance via reduced 2-ME production.111 Regulation of COMT Oestrogen reduces COMT and thus dopamine degradation by COMT in the PFC

Oestrogen reduces 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.69
COMT inhibitors (which increase the dopamine level) therefore primarily improve the executive abilities of the PFC (with excess dopamine in the PFC), but not the symptoms of hyperactivity or impulsivity in the striatum.112113
The PFC reacts to even small reductions in the availability of the dopamine precursor tyrosine with a significant decrease in dopamine, unlike other areas of the brain, e.g. the striatum, which remains unaffected.114 However, this is only relevant in phenylketonuria (PKU) and not in ADHD.
As oestrogen is a female sex hormone, women should more frequently have an elevated dopamine level in the PFC. Hypoxia, vascular occlusion and traumatic brain injury increase COMT

Hypoxia, vascular 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.115 COMT inhibitors

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 medications could therefore be helpful for ADHD - if a dopamine deficiency in the PFC is actually triggered by COMT overactivity.

COMT inhibitors are among others:

  • Serotonin hydrochloride116
  • Tolcapone (Ro 40-7592)116
  • Opicapone116
  • Flopropion (also a 5-HT1A receptor antagonist)116
  • Entacapone sodium salt11638

Salsolinol inhibits COMT.117 Salsolinol is a tetrahydroisoquinoline. COMT genetic test

A genetic test can show which COMT gene variant is present. This can indicate whether corresponding symptoms of impaired working memory result from an excess of dopamine or a lack of dopamine in the PFC.
However, as other genes also 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, could be indicated.
This knowledge could provide an indication of whether non-responding to stimulants could possibly result from increased dopamine or noradrenaline levels in the PFC.
A COMT gene test is available for around €60 (as of 2019). We do not know whether testing several genes together is cheaper.

8.2.4. Dopamine degradation through enzymatic oxidation

This presentation is based on Meiser et al.1

The 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 part. Enzymatic oxidation can occur through various enzymes:

  • MAO
  • Cyclooxygenases (COX, prostaglandin H synthase)
  • Tyrosinase and
  • other enzymes

With oxygen as the electron acceptor, these reactions generate superoxide radical anions (OO-⋅2).
The enzymatic oxidation of dopamine or L-dopa, spontaneously or by metal catalysis (Fe 3+), produces highly reactive electron-poor orthoquinones (DOPA-quinone and dopamine-quinone). DOPA quinone and dopamine quinone react easily with nucleophiles. Both quinones and ROS can react non-specifically with many cellular components and alter their functionality, which is potentially neurodegenerative. Dopamine degradation by monoamine oxidase (MAO-A, MAO-B)

Dopamine is degraded by both isoenzymes of MAO, MAO-A and MAO-B. In humans, degradation by MAO-A predominates (within the degradation by MAO) in vivo, as hardly any dopamine reaches astrocytes, where it could be degraded by MAO-B.
MAO breaks down dopamine in sending nerve endings, while COMT is active in receiving nerve endings.118

MAO breaks down dopamine into DOPAL and ROS.

DOPAL is a reactive and toxic DA metabolite. Normal physiological concentrations in dopaminergic neurons in the SN are 2-3 μM. DOPAL concentrations of more than 6 μM are toxic to many cell lines.
DOPAL can conjugate with lysine and cysteine residues and thus have a toxic effect.
DOPAL can be detoxified by aldehyde dehydrogenase or reduced by aldehyde/aldehyde reductase to the inactive 3,4-dihydroxyphenylethanol or further oxidized to non-toxic 3,4-dihydroxyphenylacetic acid.63 MAO-A

MAO-A occurs mainly in nigrostriatal dopaminergic axon terminals.119
MAO-A breaks down various monoamines119

  • Dopamine38
    • Rats:
      • 60% of dopamine degradation in the cortex by MAO-A, 40% by MAO-B120121
      • in the striatum122
        • MAO-A, but not MAO-B, contributes mainly to striatal dopamine degradation in rats
        • MAO-B, but not MAO-A, is responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum
        • MAO-B mediates GABA synthesis, upregulation of which can cause Parkinson’s motor symptoms, so MAO-B inhibitors could address Parkinson’s symptoms in this way
    • People:
      • in vitro in the cortex 30 % through MAO-A, 70 % through MAO-B123
      • but: there is hardly any DAT in astrocytes, so that in vivo only little dopamine reaches them, where it could be degraded by MAO-B119
      • People with different MAO-A gene variants show different symptoms associated with dopamine, whereas people with different MAO-B gene variants hardly show any symptoms at all
  • Adrenalin
  • Noradrenaline
  • Melatonin
  • Serotonin MAO-B

MAO-B is found in astrocytes and serotonergic neurons,119 in histaminergic neurons and outside the nervous system in blood platelets and lymphocytes.124
MAO-B controls the breakdown of119

  • Phenylethylamine
  • Benzylamine
  • Dopamine
    • in rats:
      • in the cortex 40 % through MAO-B, 60 % through MAO-A120121
      • in the striatum: no MAO-B122
        • MAO-A, but not MAO-B, contributes mainly to striatal dopamine degradation in rats
        • MAO-B, but not MAO-A, is responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum
        • MAO-B mediates GABA synthesis, upregulation of which can cause Parkinson’s motor symptoms, so MAO-B inhibitors could address Parkinson’s symptoms in this way
    • in humans:
      • in vitro in the cortex 70 % through MAO-B, 30 % through MAO-A123
        • but: there is hardly any DAT in astrocytes, so that in vivo only little dopamine reaches them, where it could be degraded by MAO-B119
        • on the other hand: Astrocytes (like microglia) can synthesize and metabolize dopamine themselves.125 Astrocytes and microglia are in direct contact with dopaminergic nerve cells. It is possible that glial cells are involved in maintaining dopamine levels in the brain in both healthy and pathological conditions. However, astrocytes are not able to convert L-DOPA that they absorb into dopamine.
    • MAO-B is upregulated in the brain of people with Parkinson’s disease
      • resulting in excessive DA degradation, which contributes to the development of Parkinson’s disease
      • irreversible MAO-B inhibitors (selegiline, rasagiline) are (limitedly) effective in Parkinson’s disease
      • mAO-B inhibition also prevents the formation and transfer of α-synuclein aggregates126
    • mAO-B increases with age127 Inhibition of the MAO

Inhibiting the MAO indirectly leads to an inhibition of the breakdown of dopamine, noradrenaline, serotonin and adrenaline and thus increases these neurotransmitters.

MAO inhibitors are:128

  • Rasagiline
  • Selegiline
  • Safinamide
  • Tranylcypromine
  • Phenelzine
  • Moclobemide
  • Isocarboxazid
  • Salsolinol117 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).129
  • Lazabemide (development discontinued)
  • Harmaline (indole alkaloid, not used as a medicinal substance)

8.2.5. Dopamine degradation by dopamine β-hydroxylase (DBH) to noradrenaline

Dopamine β-hydroxylase is a copper-dependent mono-oxygenase, an enzyme that converts dopamine into noradrenaline.
DBH polymorphisms are associated with:130

  • ADHD
  • Parkinson’s disease
  • Alzheimer’s disease
  • Schizophrenia

Dopamine and noradrenaline levels are altered in copper metabolism disorders. Infants with Menkes disease, which is caused by an ATP7A gene defect, exhibit a pronounced copper deficiency in the brain. The impaired copper supply to the CNS in these patients is associated with higher levels of dopamine and lower levels of noradrenaline in the brain and plasma, 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 reduced activity. Restoration of ATP7A expression in the mouse model of Menkes disease corrects the dopamine-norepinephrine ratio, especially when accompanied by additional copper injections.131
However, ATP7A has not yet been identified as a gene candidate for ADHD.

Salsolinol inhibits dopamine β-hydroxylase.117
Bleomycin is a potent inhibitor of dopamine β-hydroxylase.132

8.2.6. Dopamine degradation through sulfation (using sulfotransferases) Sulfation deactivates dopamine to dopamine sulfate

The sulfation of dopamine causes the active dopamine to break down into inactive dopamine sulfate.
The sulfation of dopamine and other catecholamines and bioamines serves to modulate and transport them.
It is much more pronounced and important in humans than in rodents.133 Sulfoconjugation is the most important form of dopamine inactivation in human serum, while glucuronidation predominates in rats. Thus, no ortholog of SULT1A3 is known in rodents134
Human plasma dopamine sulphate is mainly derived from the sulphoconjugation of dopamine, which is synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous factors affect plasma adopamine 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”.135

The dopamine sulphate serum level (approx. 5 ng/ml) is 10 to 15 times higher than the levels of free dopamine (0.3 ng/ml), noradrenaline (0.2 ng/ml) or adrenaline (0.05 ng/ml). Dopamine sulphate is not detectable by routine analytical methods and requires special extraction procedures.136 After the first meal after fasting, serum dopamine sulfate levels increase 50-fold. Food intake appears to stimulate peripheral dopamine synthesis and/or dopamine sulfoconjugation in the gastrointestinal tract.136 Sulfotransferases

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:136

  • SULT1 (phenol sulfotransferases or PST)
    • consists of 6 homodimeric enzymes
    • SULT1A3
      • has a high specificity for both catecholamines and catechol estrogens [29]
      • A single amino acid substitution (Glu 146) gives the enzyme a higher affinity for DA than for NE or Epi [34].
      • high mirror in
        • Gastrointestinal tract
      • moderate mirror in
        • Liver
        • Lung
        • Pancreas
        • Blood platelets
  • SULT2 (steroid sulfotransferases)

SULT are found in a variety of human tissues:

  • Liver
  • Intestine
  • Brain (PST)137
    • high mirrors:
      • temporal cortex
      • frontal cortex
    • low levels (approx. 1/10):
      • Parietal lobe
      • Occipital lobe
      • Amygdala
      • Hypothalamus
      • Hippocampus
    • lowest mirror:
      • Nucleus accumbens
      • Caudate nucleus
      • Substantia nigra Sulfotransferases and dopamine

PST appears to be an important regulator of dopamine storage and dopamine metabolism.
L-dopa altered PST in Parkinson’s patients136

  • greatly reduced in
    • Hypothalamus
    • frontal cortex
    • temporal cortex
    • Amygdala
    • occipital cortex
    • parietal cortex
  • slightly reduced in
    • Hippocampus
    • Nucleus accumbens
    • Putamen
    • Substantia nigra
  • unchanged in the
    • Meynert nucleus (nucleus basalis)
  • doubled in the
    • Caudate nucleus Sulfatases reactivate dopamine sulfate to dopamine

Sulfoconjugation is reversible by sulfatases (unlike glucuronidation, which is irreversible).138
Sulfatases convert the biologically inactive dopamine sulfate into an unconjugated, active dopamine.
To date, 17 sulphatases are known in humans. These are mainly located in the lysosomes.

  • Arylsulfatases
    • Arylsulfatase A (ARSA)
    • Arylsulfatase B (ARSB)
    • Arylsulfatase C (estrone/dehydroepiandrosterone sulfatase; steroid sulfatase, STS)
    • Arylsulfatases Dbis K
  • Iduronate-2-sulfatase Sulphation and ADHD

Arylsulfatase C (STS) is associated with inattention, cognitive problems and other ADHD symptoms.139140141142

Arylsulfatase C (STS, steroid sulfatase) cleaves sulfate groups from steroid hormones, which alters their biological activity. This also affects dehydroepiandrosterone sulphate (DHEAS).
Sulphated and non-sulphated steroids can affect GABA-A and NMDA receptors in the brain.143 Both DHEAS and its non-sulphated form DHEA inhibit the GABA-A receptor and activate the NMDA receptor.144
More about DHEA at DHEA in the chapter Neurological aspects / Hormones in ADHD.

8.2.7. Dopamine degradation through glucuronidation (by means of glucuronosyltransferases)

UDP-glucuronosyltransferases (UGTs) are involved in the detoxification of xenobiotics. They therefore help to protect the organism from dangerous 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 without a blood-brain barrier, such as the circumventricle, pineal gland, pituitary gland and neuro-olfactory tissue.145 In addition to their key role as a detoxification barrier, UGTs are also involved in maintaining the balance of endogenous compounds such as steroids or DA. Only the UGT isoform UGT1A10 is able to catalyze the glucuronidation of dopamine to a significant extent in humans. This produces dopamine-4-O-glucuronide and dopamine-3-O-glucuronide. However, UGT1A10 is not found in the human brain, only the isoforms 1A, 2A, 2B and 3A. Therefore, according to current knowledge, UGTs are not involved in dopamine metabolism in the human brain.146

8.3. Dopamine removal by diffusion

In the DAT-KO mouse, inhibition of serotonin transporters, noradrenaline transporters, MAO-A or COMT did not alter dopamine degradation in the striatum. In the absence of DAT in the striatum, this appears to occur more by diffusion.26

8.4. Conclusions for the medication of ADHD

8.4.1. 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 an inhibition of the activity of the respective transporters.9
The noradrenaline transporter - along with COMT - is responsible for most dopamine degradation in the PFC, while the DAT regulates this mainly in the striatum.

Binding affinity: stronger with smaller number (KD = Ki) DAT NET SERT
MPH 34 - 200 339 > 10,000
d-AMP (Elvanse, Attentin) 34 - 41 23.3 - 38.9 3,830 - 11,000
l-AMP 138 30.1 57,000
ATX 1451 - 1600 2.6 - 5 48 - 77

8.4.2. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region

The active substances methylphenidate (MPH), amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,9 modified.

PFC Striatum Nucleus accumbens
NE (+)
DA +
NE +/- 0
DA +
NE +/- 0
NE +
DA +
NE +/- 0
DA +
NE +/- 0
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.

  1. Meiser, Weindl, Hiller (2013): Complexity of dopamine metabolism. Cell Commun Signal. 2013 May 17;11(1):34. doi: 10.1186/1478-811X-11-34. PMID: 23683503; PMCID: PMC3693914. REVIEW

  2. Daws LC (2021): Organic Cation Transporters in Psychiatric Disorders. Handb Exp Pharmacol. 2021;266:215-239. doi: 10.1007/164_2021_473. PMID: 34282486; PMCID: PMC9281871.

  3. Floresco SB, West AR, Ash B, Moore H, Grace AA (2003): Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci. 2003 Sep;6(9):968-73. doi: 10.1038/nn1103. PMID: 12897785.

  4. Giros Jaber, Jones, Wightman, Caron (1996): Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996 Feb 15;379(6566):606-12. doi: 10.1038/379606a0. PMID: 8628395.

  5. DiCarlo, Aguilar, Matthies, Harrison, Bundschuh, West, Hashemi, Herborg, Rickhag, Chen, Gether, Wallace, Galli (2019): Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. J Clin Invest. 2019 May 16;129(8):3407-3419. doi: 10.1172/JCI127411. PMID: 31094705; PMCID: PMC6668686.

  6. Sulzer, Cragg, Rice (2016): Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. 2016 Aug;6(3):123-148. doi: 10.1016/j.baga.2016.02.001. PMID: 27141430; PMCID: PMC4850498.

  7. Diamond (2011): Biological and social influences on cognitive control processes dependent on prefrontal cortex. Prog Brain Res. 2011;189:319-39. doi: 10.1016/B978-0-444-53884-0.00032-4. PMID: 21489397; PMCID: PMC4103914. REVIEW

  8. Holleran KM, Rose JH, Fordahl SC, Benton KC, Rohr KE, Gasser PJ, Jones SR (2020): Organic cation transporter 3 and the dopamine transporter differentially regulate catecholamine uptake in the basolateral amygdala and nucleus accumbens. Eur J Neurosci. 2020 Dec;52(11):4546-4562. doi: 10.1111/ejn.14927. PMID: 32725894; PMCID: PMC7775350.

  9. Madras, Miller, Fischman (2005): The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005 Jun 1;57(11):1397-409. doi: 10.1016/j.biopsych.2004.10.011. PMID: 15950014.

  10. Green, Eid, Zhan, Zarbl, Guo, Richardson (2019): Epigenetic Regulation of the Ontogenic Expression of the Dopamine Transporter. Front Genet. 2019 Nov 4;10:1099. doi: 10.3389/fgene.2019.01099. eCollection 2019.

  11. Hovde MJ, Larson GH, Vaughan RA, Foster JD (2019): Model systems for analysis of dopamine transporter function and regulation. Neurochem Int. 2019 Feb;123:13-21. doi: 10.1016/j.neuint.2018.08.015. PMID: 30179648; PMCID: PMC6338519. REVIEW

  12. Waldman, Rowe, Abramowitz, Kozel, Mohr, Sherman, Cleveland, Sanders, Gard, Stever (1998): Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet. 1998 Dec;63(6):1767-76. doi: 10.1086/302132. PMID: 9837830; PMCID: PMC1377649.

  13. Doucette-Stamm, Blakely, Tian, Mockus, Mao (1995): Population genetic study of the human dopamine transporter gene (DAT1). Genet Epidemiol. 1995;12(3):303-8. doi: 10.1002/gepi.1370120307. PMID: 7557351.

  14. Lee FJ, Pei L, Moszczynska, Vukusic, Fletcher, Liu F (2007): Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor. EMBO J. 2007 Apr 18;26(8):2127-36. doi: 10.1038/sj.emboj.7601656. PMID: 17380124; PMCID: PMC1852782.

  15. Khoshbouei H, Sen N, Guptaroy B, Johnson L’, Lund D, Gnegy ME, Galli A, Javitch JA (2004): N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol. 2004 Mar;2(3):E78. doi: 10.1371/journal.pbio.0020078. PMID: 15024426; PMCID: PMC368172.

  16. Granas C, Ferrer J, Loland CJ, Javitch JA, Gether U (2003): N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P receptor-stimulated phosphorylation without impairing transporter internalization. J Biol Chem. 2003 Feb 14;278(7):4990-5000. doi: 10.1074/jbc.M205058200. PMID: 12464618.

  17. Tammimaki, Aonurm-Helm, Zhang, Poutanen, Duran-Torres, Garcia-Horsman, Mannisto (2016): Generation of membrane-bound catechol-O-methyl transferase deficient mice with disctinct sex dependent behavioral phenotype. J Physiol Pharmacol. 2016 Dec;67(6):827-842.

  18. Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation

  19. Ingram, Prasad, Amara (2005): Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci. 2002 Oct;5(10):971-8. doi: 10.1038/nn920. PMID: 12352983.

  20. Vaughan RA, Foster JD (2013): Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci. 2013 Sep;34(9):489-96. doi: 10.1016/ PMID: 23968642; PMCID: PMC3831354. REVIEW

  21. Carvelli L, McDonald PW, Blakely RD, DeFelice LJ (2004):Dopamine transporters depolarize neurons by a channel mechanism. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16046-51. doi: 10.1073/pnas.0403299101. PMID: 15520385; PMCID: PMC528740.

  22. Shoblock, Maisonneuve, Glick (2004): Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex. Neurochem Res. 2004 Jul;29(7):1437-42. doi: 10.1023/b:nere.0000026409.76261.f3. PMID: 15202777.

  23. Carboni, Tanda, Frau, Di Chiara (1990): Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem. 1990 Sep;55(3):1067-70. doi: 10.1111/j.1471-4159.1990.tb04599.x. PMID: 2117046.

  24. Ulke, Rullmann, Huang, Luthardt, Becker, Patt, Meyer, Tiepolt, Hesse, Sabri, Strauß (2019): Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study. Transl Psychiatry. 2019 Nov 15;9(1):301. doi: 10.1038/s41398-019-0619-y.

  25. Morón, Brockington, Wise, Rocha, Hope (2002): Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci. 2002 Jan 15;22(2):389-95. doi: 10.1523/JNEUROSCI.22-02-00389.2002. PMID: 11784783; PMCID: PMC6758674.

  26. Jones, Gainetdinov, Jaber, Giros, Wightman, Caron (1998): Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34. doi: 10.1073/pnas.95.7.4029. PMID: 9520487; PMCID: PMC19957.

  27. Sagheddu C, Cancedda E, Bagheri F, Kalaba P, Muntoni AL, Lubec J, Lubec G, Sanna F, Pistis M (2023): The atypical dopamine transporter inhibitor CE-158 enhances dopamine neurotransmission in the prefrontal cortex of male rats: a behavioral, electrophysiological and microdialysis study. Int J Neuropsychopharmacol. 2023 Sep 19:pyad056. doi: 10.1093/ijnp/pyad056. Epub ahead of print. PMID: 37725477.

  28. Muhammed Ajeebsanu M, Subhahar MB, Karakka Kal AK, Philip M, Perwad Z, Karatt TK, Graiban FM, Joseph M, Jose SV (2024): Comprehensive metabolic investigation of dopamine reuptake inhibitor HDMP-28 in equine liver microsomes and Cunninghamella elegans for doping control. Drug Test Anal. 2024 Jan 15. doi: 10.1002/dta.3642. PMID: 38225724.

  29. Gasser PJ (2019): Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior. Neurochem Int. 2019 Feb;123:46-49. doi: 10.1016/j.neuint.2018.07.008. PMID: 30055194; PMCID: PMC6338509.

  30. Lightman SL, Iversen LL (1969): The role of uptake2 in the extraneuronal metabolism of catecholamines in the isolated rat heart. Br J Pharmacol. 1969 Nov;37(3):638-49. doi: 10.1111/j.1476-5381.1969.tb08502.x. PMID: 5348467; PMCID: PMC1703732.

  31. Duan, Wang (2010): Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. PMID: 20858707; PMCID: PMC2993547.

  32. Engel K, Zhou M, Wang J (2004): Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem. 2004 Nov 26;279(48):50042-9. doi: 10.1074/jbc.M407913200. PMID: 15448143.

  33. Yoshikawa T, Nakamura T, Yanai K (2019): Histamine N-Methyltransferase in the Brain. Int J Mol Sci. 2019 Feb 10;20(3):737. doi: 10.3390/ijms20030737. PMID: 30744146; PMCID: PMC6386932. REVIEW

  34. Duan H, Wang J (2013): Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene. J Biol Chem. 2013 Feb 1;288(5):3535-44. doi: 10.1074/jbc.M112.436972. PMID: 23255610; PMCID: PMC3561572.

  35. DocCheck Flexikon: Plexus choroidei

  36. Adamsen D, Ramaekers V, Ho HT, Britschgi C, Rüfenacht V, Meili D, Bobrowski E, Philippe P, Nava C, Van Maldergem L, Bruggmann R, Walitza S, Wang J, Grünblatt E, Thöny B (2014): Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. Mol Autism. 2014 Aug 13;5:43. doi: 10.1186/2040-2392-5-43. PMID: 25802735; PMCID: PMC4370364.

  37. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S (2006): Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52. doi: 10.1016/j.neuropharm.2006.01.005. PMID: 16581093.}}) aufgenommen. Diese Uptake-2-Transporter werden auch als Solute carrier family 22 member 1/2/3 oder Extraneuronale Monoamin-Transporter (EMT) bezeichnet. OTC2 und OTC3 finden sich in Nervenzellen und Astrozyten und binden Histamin > Noradrenalin und Adrenalin > Dopamin > Serotonin.{{Duan, Wang (2010): Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. PMID: 20858707; PMCID: PMC2993547.

  38. Böhm (2020): Dopaminerge Systeme, in: Freissmuth, Offermanns, Böhm (Herausgeber): Pharmakologie und Toxikologie. Von den molekularen Grundlagen zur Pharmakotherapie.

  39. Koepsell (2021): General Overview of Organic Cation Transporters in Brain. Handb Exp Pharmacol. 2021;266:1-39. doi: 10.1007/164_2021_449. PMID: 33782773.

  40. Haenisch B, Drescher E, Thiemer L, Xin H, Giros B, Gautron S, Bönisch H (2012): Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):1017-23. doi: 10.1007/s00210-012-0781-8. PMID: 22806583.

  41. Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH (2003): Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 2003 Nov;23(21):7902-8. doi: 10.1128/MCB.23.21.7902-7908.2003. PMID: 14560032; PMCID: PMC207626.

  42. Yoshikawa T, Naganuma F, Iida T, Nakamura T, Harada R, Mohsen AS, Kasajima A, Sasano H, Yanai K (2013): Molecular mechanism of histamine clearance by primary human astrocytes. Glia. 2013 Jun;61(6):905-16. doi: 10.1002/glia.22484. PMID: 23505051.

  43. Koepsell H, Lips K, Volk C (2007): Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res. 2007 Jul;24(7):1227-51. doi: 10.1007/s11095-007-9254-z. PMID: 17473959. REVIEW

  44. Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A, Louis F, Vialou V, Martres MP, Chevarin C, Hamon M, Giros B, Gautron S (2012): Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry. 2012 Sep;17(9):926-39. doi: 10.1038/mp.2011.87. PMID: 21769100.

  45. Couroussé T, Bacq A, Belzung C, Guiard B, Balasse L, Louis F, Le Guisquet AM, Gardier AM, Schinkel AH, Giros B, Gautron S (2015): Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling. Mol Psychiatry. 2015 Jul;20(7):889-900. doi: 10.1038/mp.2014.86. PMID: 25092247.

  46. Naganuma F, Yoshikawa T (2021): Organic Cation Transporters in Brain Histamine Clearance: Physiological and Psychiatric Implications. Handb Exp Pharmacol. 2021;266:169-185. doi: 10.1007/164_2021_447. PMID: 33641029. REVIEW

  47. Gasser PJ (2019): Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior. Neurochem Int. 2019 Feb;123:46-49. doi: 10.1016/j.neuint.2018.07.008. PMID: 30055194; PMCID: PMC6338509. REVIEW

  48. Gasser PJ, Lowry CA (2018): Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior. Horm Behav. 2018 Aug;104:173-182. doi: 10.1016/j.yhbeh.2018.05.003. PMID: 29738736; PMCID: PMC7137088. REVIEW

  49. Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S (2008): Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem. 2008 Aug;106(3):1471-82. doi: 10.1111/j.1471-4159.2008.05506.x. PMID: 18513366.

  50. Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, Jackson-Lewis V, Javitch JA, Ballatori N, Przedborski S, Tieu K (2009): The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci U S A. 2009 May 12;106(19):8043-8. doi: 10.1073/pnas.0900358106. PMID: 19416912; PMCID: PMC2683105.

  51. Hill JE, Makky K, Shrestha L, Hillard CJ, Gasser PJ (2011): Natural and synthetic corticosteroids inhibit uptake 2-mediated transport in CNS neurons. Physiol Behav. 2011 Aug 3;104(2):306-11. doi: 10.1016/j.physbeh.2010.11.012. PMID: 21081135.

  52. Volk C, Gorboulev V, Kotzsch A, Müller TD, Koepsell H (2009): Five amino acids in the innermost cavity of the substrate binding cleft of organic cation transporter 1 interact with extracellular and intracellular corticosterone. Mol Pharmacol. 2009 Aug;76(2):275-89. doi: 10.1124/mol.109.054783. PMID: 19435783.

  53. Scholl JL, Solanki RR, Watt MJ, Renner KJ, Forster GL (2023): Chronic administration of glucocorticoid receptor ligands increases anxiety-like behavior and selectively increase serotonin transporters in the ventral hippocampus. Brain Res. 2023 Feb 1;1800:148189. doi: 10.1016/j.brainres.2022.148189. PMID: 36462646; PMCID: PMC9837808.

  54. Chen EC, Matsson P, Azimi M, Zhou X, Handin N, Yee SW, Artursson P, Giacomini KM (2022): High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3. Pharm Res. 2022 Jul;39(7):1599-1613. doi: 10.1007/s11095-022-03171-8. PMID: 35089508; PMCID: PMC9246766.

  55. Angenoorth TJF, Stankovic S, Niello M, Holy M, Brandt SD, Sitte HH, Maier J (2021): Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1-3 and Human Plasma Membrane Monoamine Transporter. Int J Mol Sci. 2021 Nov 30;22(23):12995. doi: 10.3390/ijms222312995. PMID: 34884800; PMCID: PMC8657792.

  56. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S (2006): Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52. doi: 10.1016/j.neuropharm.2006.01.005. PMID: 16581093.

  57. Kitaichi K, Fukuda M, Nakayama H, Aoyama N, Ito Y, Fujimoto Y, Takagi K, Takagi K, Hasegawa T (2005): Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice. Neurosci Lett. 2005 Jul 1-8;382(1-2):195-200. doi: 10.1016/j.neulet.2005.03.014. PMID: 15911148.

  58. Nakayama H, Kitaichi K, Ito Y, Hashimoto K, Takagi K, Yokoi T, Takagi K, Ozaki N, Yamamoto T, Hasegawa T (2007): The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats. Brain Res. 2007 Dec 12;1184:260-9. doi: 10.1016/j.brainres.2007.09.072. PMID: 17988657.

  59. Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF, Gründemann D, Schömig E, Lesch KP, Gerlach M, Reif A (2009): Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm (Vienna). 2009 Jun;116(6):689-97. doi: 10.1007/s00702-009-0205-1. PMID: 19280114.

  60. Schildkraut JJ, Mooney JJ (2004): Toward a rapidly acting antidepressant: the normetanephrine and extraneuronal monoamine transporter (uptake 2) hypothesis. Am J Psychiatry. 2004 May;161(5):909-11. doi: 10.1176/appi.ajp.161.5.909. PMID: 15121658.

  61. Orrico-Sanchez A, Chausset-Boissarie L, Alves de Sousa R, Coutens B, Rezai Amin S, Vialou V, Louis F, Hessani A, Dansette PM, Zornoza T, Gruszczynski C, Giros B, Guiard BP, Acher F, Pietrancosta N, Gautron S (2020): Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression. Mol Psychiatry. 2020 Jun;25(6):1245-1259. doi: 10.1038/s41380-019-0548-4. PMID: 31619760.

  62. Zhou Z, Thevapriya S, Chao YX, Lim TM, Tan EK (2016): Dopamine (DA) dependent toxicity relevant to DA neuron degeneration in Parkinson’s disease (PD) Austin J Drug Abuse Addict. 2016;3:1010–1018.

  63. Zhou ZD, Yi LX, Wang DQ, Lim TM, Tan EK (2023): Role of dopamine in the pathophysiology of Parkinson’s disease. Transl Neurodegener. 2023 Sep 18;12(1):44. doi: 10.1186/s40035-023-00378-6. PMID: 37718439; PMCID: PMC10506345. REVIEW

  64. DocCheck Flexikon: Metabolisierung

  65. Xu H, Yang F (2022): The interplay of dopamine metabolism abnormalities and mitochondrial defects in the pathogenesis of schizophrenia. Transl Psychiatry. 2022 Nov 7;12(1):464. doi: 10.1038/s41398-022-02233-0. PMID: 36344514; PMCID: PMC9640700. REVIEW

  66. Jones DC, Gunasekar PG, Borowitz JL, Isom GE (2000): Dopamine-induced apoptosis is mediated by oxidative stress and Is enhanced by cyanide in differentiated PC12 cells. J Neurochem. 2000 Jun;74(6):2296-304. doi: 10.1046/j.1471-4159.2000.0742296.x. PMID: 10820189.

  67. Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM (2009): Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci. 2009 Apr;123(2):418-29. doi: 10.1037/a0014477. PMID: 19331464.

  68. Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG (2019): Dopamine: Functions, Signaling, and Association with Neurological Diseases. Cell Mol Neurobiol. 2019 Jan;39(1):31-59. doi: 10.1007/s10571-018-0632-3. PMID: 30446950. REVIEW

  69. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 21

  70. Durston, Fossella, Casey, Hulshoff, Galvan, Schnack, Steenhuis, Minderaa, Buitelaar, Kahn, van Engeland (2005): Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry. 2005 Jul;10(7):678-85.

  71. Lewis, Melchitzky, Scsack, Whitehead, Sampson (2001): Dopamine transporter immunoreactivity in monkey cerebral cortex: Regional, laminar, and ultrastructurallocalisation. 71re Journal of Comparative Neurology, 432, 119-136.

  72. Sesack, Hawrylak, Matus, Guido, Levey (1998): Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopaminetransporter. The Journal of Neuroscience, 18,2697-2708.

  73. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 27

  74. Napolitano, Cesura, Da Prada (1995): The role of monoamine oxidase and catechol O-methyltransferase in dopaminergic neurotransmission. J Neural Transm Suppl. 1995;45:35-45

  75. Weinshilboum, Otterness, Szumlanski (1999): Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol. 1999;39:19-52.

  76. Karoum, Chrapusta, Egan (1994): 3-Methoxytyramine Is the Major Metabolite of Released Dopamine in the Rat Frontal Cortex: Reassessment of the Effects of Antipsychotics on the Dynamics of Dopamine Release and Metabolism in the Frontal Cortex, Nucleus Accumbens, and Striatum by a Simple Two Pool Model. Journal of Neurochemistry, 63: 972–979. doi:10.1046/j.1471-4159.1994.63030972.x

  77. Broome, Louangaphay, Keay, Leggio, Musumeci, Castorina (2020): Dopamine: an immune transmitter. Neural Regen Res. 2020 Dec;15(12):2173-2185. doi: 10.4103/1673-5374.284976. PMID: 32594028; PMCID: PMC7749467. REVIEW)

  78. Królicka, Kieć-Kononowicz, Łażewska (2022): Chalcones as Potential Ligands for the Treatment of Parkinson’s Disease. Pharmaceuticals (Basel). 2022 Jul 10;15(7):847. doi: 10.3390/ph15070847. PMID: 35890146; PMCID: PMC9317344. REVIEW

  79. Simpson, Morud, Winiger, Biezonski, Zhu, Bach, Malleret, Polan, Ng-Evans, Phillips, Kellendonk, Kandel (2014): Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum; Learn Mem. 2014 Apr; 21(4): 205–214. doi: 10.1101/lm.032094.113, PMCID: PMC3966542

  80. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 28

  81. Heinz, Smolka (2006): The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks. Rev Neurosci. 2006;17(3):359-67.

  82. Colzato, Waszak, Nieuwenhuis, Posthuma, Hommel (2010): The flexible mind is associated with the catechol-O-methyltransferase (COMT) Val158Met polymorphism: evidence for a role of dopamine in the control of task-switching. Neuropsychologia. 2010 Jul;48(9):2764-8. doi: 10.1016/j.neuropsychologia.2010.04.023. PMID: 20434465. n = 87

  83. Millenet, Nees, Heintz, Bach, Frank, Vollstädt-Klein, Bokde, Bromberg, Büchel, Quinlan, Desrivières, Fröhner, Flor, Frouin, Garavan, Gowland, Heinz, Ittermann, Lemaire, Martinot, Martinot, Papadoulos, Paus, Poustka, Rietschel, Smolka, Walter, Whelan, Schumann, Banaschewski, Hohmann (2018): COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents. Front Genet. 2018 Jul 31;9:284. doi: 10.3389/fgene.2018.00284. eCollection 2018. n = 462

  84. Zubieta, Heitzeg, Smith, Bueller, Ke Xu, Yanjun Xu, Koeppe, Stohler, Goldman (2003): COMT val158met Genotype Affects µ-Opioid Neurotransmitter Responses to a Pain Stressor; Science 21 Feb 2003: Vol. 299, Issue 5610, pp. 1240-1243; DOI: 10.1126/science.1078546

  85. Diatchenko, Slade, Nackley, Bhalang, Sigurdsson, Belfer, Goldman, Xu, Shabalina, Shagin, Max, Makarov, Maixner (2005): Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43.

  86. Caspi, Moffitt, Cannon, McClay, Murray, Harrington, Taylor, Arseneault, Williams, Braithwaite, Poulton, Craig (2005): Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005 May 15;57(10):1117-27.

  87. Howes, McCutcheon, Owen, Murray (2017): The role of genes, stress and dopamine in the development of schizophrenia; Biol Psychiatry. 2017 Jan 1; 81(1): 9–20. doi: 10.1016/j.biopsych.2016.07.014, PMCID: PMC5675052; EMSID: EMS74692

  88. Ferenczi, Zalocusky, Liston, Grosenick, Warden, Amatya, Katovich, Mehta, Patenaude, Ramakrishnan, Kalanithi, Etkin, Knutson, Glover, Deisseroth (2016): Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science. 2016 Jan 1;351(6268):aac9698. doi: 10.1126/science.aac9698

  89. Rosa, Dickinson, Apud, Weinberger, Elvevåg (2010): COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination. Behav Brain Funct. 2010 Sep 13;6:53. doi: 10.1186/1744-9081-6-53.

  90. Müller (2010):Depression bei umweltbedingten Erkrankungen, Umwelt-Medizin-Gesellschaft, 23, Heft 4/2010, 294 -308

  91. Berman, Narasimhan, Miller, Anand, Cappiello, Oren, Heninger, Charney (1999): Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker? Arch Gen Psychiatry. 1999 May;56(5):395-403. doi: 10.1001/archpsyc.56.5.395. PMID: 10232292.

  92. Reuter, Hennig (2005): Association of the functional catechol-O-methyltransferase VAL158MET polymorphism with the personality trait of extraversion. Neuroreport. 2005 Jul 13;16(10):1135-8.

  93. Reuter, Frenzel, Walter, Markett, Montag (2011): Investigating the genetic basis of altruism: the role of the COMT Val158Met polymorphism. Soc Cogn Affect Neurosci. 2011 Oct;6(5):662-8. doi: 10.1093/scan/nsq083. PMID: 21030481; PMCID: PMC3190209. n = 101

  94. Goldberg, Weinberger (2004): Genes and the parsing of cognitive processes. Trends Cogn Sci. 2004 Jul;8(7):325-35. doi: 10.1016/j.tics.2004.05.011. PMID: 15242692. REVIEW

  95. Tunbridge, Harrison, Weinberger (2005)_ Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006 Jul 15;60(2):141-51. doi: 10.1016/j.biopsych.2005.10.024. PMID: 16476412. REVIEW

  96. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 29

  97. Akutagava-Martins, Salatino-Oliveira, Kieling, Genro, Polanczyk, Anselmi, Menezes, Gonçalves, Wehrmeister, Barros, Callegari-Jacques, Rohde, Hutz (2016): COMT and DAT1 genes are associated with hyperactivity and inattention traits in the 1993 Pelotas Birth Cohort: evidence of sex-specific combined effect. J Psychiatry Neurosci. 2016 Oct;41(6):405-412. n = 4101

  98. Levy (2007): What do dopamine transporter and catechol-o-methyltransferase tell us about attention deficit-hyperactivity disorder? Pharmacogenomic implications. Aust N Z J Psychiatry. 2007 Jan;41(1):10-6.

  99. Bellgrove, Domschke, Hawi, Kirley, Mullins, Robertson, Gill ( The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD. Exp Brain Res. 2005 Jun;163(3):352-60. doi: 10.1007/s00221-004-2180-y. PMID: 15654584.

  100. Stitzinger (2006): Der Einfluss genetischer Variationen im COMT Gen auf kognitive Phänotypen. Dissertation. S. 32

  101. Mattay, Goldberg, Fera, Hariri, Tessitore, Egan, Kolachana, Callicott, Weinberger (2003): Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. doi: 10.1073/pnas.0931309100. PMID: 12716966; PMCID: PMC156347.

  102. de Frias, Marklund, Eriksson, Larsson, Oman, Annerbrink, Bäckman, Nilsson, Nyberg (2010): Influence of COMT gene polymorphism on fMRI-assessed sustained and transient activity during a working memory task. J Cogn Neurosci. 2010 Jul;22(7):1614-22. doi: 10.1162/jocn.2009.21318.

  103. Mizuno, Jung, Fujisawa, Takiguchi, Shimada, Saito, Kosaka, Tomoda (2017): Catechol-O-methyltransferase polymorphism is associated with the cortico-cerebellar functional connectivity of executive function in children with attention-deficit/hyperactivity disorder. Sci Rep. 2017 Jul 7;7(1):4850. doi: 10.1038/s41598-017-04579-8.

  104. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis, Seite 27

  105. Simpson, Morud, Winiger, Biezonski, Zhu, Bach, Malleret, Polan, Ng-Evans, Phillips, Kellendonk, Kandel (2014): Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum; Learn Mem. 2014 Apr; 21(4): 205–214. Published online 2014 Apr. doi: 10.1101/lm.032094.113, PMCID: PMC3966542

  106. Tadić, Victor, Başkaya, von Cube, Hoch, Kouti, Anicker, Höppner, Lieb, Dahmen (2009): Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder. Am. J. Med. Genet., 150B: 487–495. doi:10.1002/ajmg.b.30843, n = 317

  107. Brackmann (2005): Jenseits der Norm – Hoch begabt und hoch sensibel, Klett-Cotta, S. 187 ff

  108. Tsao (2011): Identifying molecular mechanisms of catechol o-methyltransferase activity and regulation, Dissertation

  109. Shekim, Antun, Hanna, McCracken, Hess (1990). S-adenosyl-L-methionine (SAM) in adults with ADHD, RS: Preliminary results from an open trial. Psychopharmacology Bulletin, 26(2), 249-253. n = 8

  110. Tchivileva, Nackley, Qian, Wentworth, Conrad, Diatchenko (2009): Characterization of NF-kB-mediated inhibition of catechol-O-methyltransferase. Molecular Pain20095:13

  111. Kanasaki, Srivastava, Yang, Xu, Kudoh, Kitada, Ueki, Kim, Li, Takeda, Kanasaki, Koya (2017): Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice. Scientific Reports Volume 7, Article number: 7927 2017

  112. Gasparini, Fabrizio, Bonifati, Meco (1997): Cognitive improvement during Tolcapone treatment in Parkinson’s disease; Journal of Neural Transmission; August 1997, Volume 104, Issue 8–9, pp 887–894

  113. Chong, Suchowersky, Szumlanski, Weinshilboum, Brant, Campbell (2000): The Relationship between COMT Genotype and the Clinical Effectiveness of Tolcapone, a COMT Inhibitor, in Patients with Parkinson’s Disease; Clinical Neuropharmacology: May-June 2000 – Volume 23 – Issue 3 – p 143-148

  114. Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 25

  115. Redell, Dash (2007): Traumatic brain injury stimulates hippocampal catechol-O-methyl transferase expression in microglia. Neurosci Lett. 2007 Feb 8;413(1):36-41. doi: 10.1016/j.neulet.2006.11.060. PMID: 17240060; PMCID: PMC1857315.

  116., Abruf 23.06.19

  117. Napolitano, Manini, d’Ischia (2011): Oxidation chemistry of catecholamines and neuronal degeneration: an update. Curr Med Chem. 2011;18(12):1832-45. doi: 10.2174/092986711795496863. PMID: 21466469.

  118. Rostain (2015): The Neurobiology of ADHD, Perelman School of Medicine, University of Pennsylvania

  119. Nam, Sa, Ju, Park, Lee (2022): Revisiting the Role of Astrocytic MAOB in Parkinson’s Disease. Int J Mol Sci. 2022 Apr 18;23(8):4453. doi: 10.3390/ijms23084453. PMID: 35457272; PMCID: PMC9028367. REVIEW

  120. Schoepp, Azzaro (1981): Specificity of endogenous substrates for types A and B monoamine oxidase in rat striatum. J Neurochem. 1981 Jun;36(6):2025-31. doi: 10.1111/j.1471-4159.1981.tb10829.x. PMID: 6787175.

  121. Garrick, Murphy (1980): Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain. Psychopharmacology (Berl). 1980;72(1):27-33. doi: 10.1007/BF00433804. PMID: 6781004.

  122. Cho HU, Kim S, Sim J, Yang S, An H, Nam MH, Jang DP, Lee CJ. Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis. Exp Mol Med. 2021 Jul;53(7):1148-1158. doi: 10.1038/s12276-021-00646-3. PMID: 34244591; PMCID: PMC8333267.

  123. (Garrick, Murphy (1980): Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain. Psychopharmacology (Berl). 1980;72(1):27-33. doi: 10.1007/BF00433804. PMID: 6781004.

  124. Finberg (2019): Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson’s disease. J Neural Transm (Vienna). 2019 Apr;126(4):433-448. doi: 10.1007/s00702-018-1952-7. PMID: 30386930. REVIEW

  125. Broome, Louangaphay, Keay, Leggio, Musumeci, Castorina (2020): Dopamine: an immune transmitter. Neural Regen Res. 2020 Dec;15(12):2173-2185. doi: 10.4103/1673-5374.284976. PMID: 32594028; PMCID: PMC7749467. REVIEW

  126. Nakamura, Arawaka, Sato, Sasaki, Shigekiyo, Takahata, Tsunekawa, Kato (2021): Monoamine Oxidase-B Inhibition Facilitates α-Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson’s Disease. J Neurosci. 2021 Sep 1;41(35):7479-7491. doi: 10.1523/JNEUROSCI.0476-21.2021. PMID: 34290084; PMCID: PMC8412984.

  127. Królicka, Kieć-Kononowicz, Łażewska (2022): Chalcones as Potential Ligands for the Treatment of Parkinson’s Disease. Pharmaceuticals (Basel). 2022 Jul 10;15(7):847. doi: 10.3390/ph15070847. PMID: 35890146; PMCID: PMC9317344.

  128. Monoaminoxidasehemmer; DocCheckFlexikon

  129. Ebermann, Elmadfa (2008): Lehrbuch Lebensmittelchemie und Ernährung; Springer-Verlag, 08.09.2008 – 739 Seiten, Seite 500

  130. Roy, Ghosh, Bhattacharya, Saha, Das, Gangopadhyay, Bavdekar, Ray, Sengupta, Ray (2019): Dopamine β hydroxylase (DBH) polymorphisms do not contribute towards the clinical course of Wilson’s disease in Indian patients. J Gene Med. 2019 Sep;21(9):e3109. doi: 10.1002/jgm.3109. PMID: 31265749.

  131. Lutsenko, Washington-Hughes, Ralle, Schmidt (2019): Copper and the brain noradrenergic system. J Biol Inorg Chem. 2019 Dec;24(8):1179-1188. doi: 10.1007/s00775-019-01737-3. PMID: 31691104; PMCID: PMC6941745.

  132. Matsui, Kato, Yamamoto, Takita, Takeuchi, Umezawa, Nagatsu (1980). Inhibition of dopamine-beta-hydroxylase, A copper enzyme, by bleomycin. J Antibiot (Tokyo). 1980 Apr;33(4):435-40. doi: 10.7164/antibiotics.33.435. PMID: 6157665.

  133. Eisenhofer, Coughtrie, Goldstein (1999): Dopamine sulphate: an enigma resolved. Clin Exp Pharmacol Physiol Suppl. 1999 Apr;26:S41-53. PMID: 10386253. REVIEW

  134. Dajani, Cleasby, Neu, Wonacott, Jhoti, Hood, Modi, Hersey, Taskinen, Cooke, Manchee, Coughtrie (1999):. X-ray crystal structure of human dopamine sulfotransferase, SULT1A3. Molecular modeling and quantitative structure-activity relationship analysis demonstrate a molecular basis for sulfotransferase substrate specificity. J Biol Chem. 1999 Dec 31;274(53):37862-8. doi: 10.1074/jbc.274.53.37862. PMID: 10608851.

  135. Goldstein, Swoboda, Miles, Coppack, Aneman, Holmes, Lamensdorf, Eisenhofer (1999): Sources and physiological significance of plasma dopamine sulfate. J Clin Endocrinol Metab. 1999 Jul;84(7):2523-31. doi: 10.1210/jcem.84.7.5864. PMID: 10404831.

  136. Ben-Jonathan (2020): Dopamine - Endocrine and Oncogenic Functions, S. 11

  137. Baran, Jellinger (1992): Human brain phenolsulfotransferase. Regional distribution in Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1992;4:267-76. doi: 10.1007/BF02260075. PMID: 1388697.

  138. Ghosh (2007): Human sulfatases: a structural perspective to catalysis. Cell Mol Life Sci. 2007 Aug;64(15):2013-22. doi: 10.1007/s00018-007-7175-y. PMID: 17558559.

  139. Stergiakouli, Langley, Williams, Walters, Williams, Suren, Giegling, Wilkinson, Owen, O’Donovan, Rujescu, Thapar, Davies (2011): Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder. Genes Brain Behav. 2011 Apr;10(3):334-44. doi: 10.1111/j.1601-183X.2010.00672.x. PMID: 21255266; PMCID: PMC3664024.

  140. Humby, Fisher, Allen, Reynolds, Hartman, Giegling, Rujescu, Davies (2017): A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males. Brain Behav. 2017 Feb 9;7(3):e00646. doi: 10.1002/brb3.646. PMID: 28293481; PMCID: PMC5346528.

  141. Davies, Humby, Kong, Otter, Burgoyne, Wilkinson (2009): Converging pharmacological and genetic evidence indicates a role for steroid sulfatase in attention. Biol Psychiatry. 2009 Aug 15;66(4):360-7. doi: 10.1016/j.biopsych.2009.01.001. PMID: 19251250; PMCID: PMC2720459.

  142. Trent, Dennehy, Richardson, Ojarikre, Burgoyne, Humby, Davies (2012): Steroid sulfatase-deficient mice exhibit endophenotypes relevant to attention deficit hyperactivity disorder. Psychoneuroendocrinology. 2012 Feb;37(2):221-9. doi: 10.1016/j.psyneuen.2011.06.006. PMID: 21723668; PMCID: PMC3242075.

  143. Compagnone, Mellon (2000): Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol. 2000 Jan;21(1):1-56. doi: 10.1006/frne.1999.0188. PMID: 10662535. REVIEW

  144. Yadid, Sudai, Maayan, Gispan, Weizman (2010): The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior. Neurosci Biobehav Rev. 2010 Nov;35(2):303-14. doi: 10.1016/j.neubiorev.2010.03.003. PMID: 20227436. REVIEW

  145. Ouzzine, Gulberti, Ramalanjaona, Magdalou, Fournel-Gigleux (2014): The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication. Front Cell Neurosci. 2014 Oct 28;8:349. doi: 10.3389/fncel.2014.00349. PMID: 25389387; PMCID: PMC4211562. REVIEW

  146. Ben-Jonathan (2020): Dopamine - Endocrine and Oncogenic Functions, S. 10

Diese Seite wurde am 23.02.2024 zuletzt aktualisiert.