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9. What regulates dopamine

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9. What regulates dopamine

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Dopamine is moderated by a variety of regulatory mechanisms. The following description is the beginning of a collection of these factors and is by no means complete.
For ADHD, the most important mechanisms are likely to be dopamine (re)uptake by the DAT, dopamine efflux into the extracellular space and the regulation of dopamine synthesis and release by the D2 autoreceptor. However, the other influences are also relevant.

9.1. Regulatory mechanisms according to brain regions

9.1.1. Mechanisms that influence DAT

Dopamine (re)uptake by the DAT is the main mechanism for regulating and terminating dopamine signaling in the brain. Dysregulated DAT function is associated with several neurological and psychiatric disorders, including ADHD, schizophrenia, Parkinson’s disease, and drug addiction. A plethora of mechanisms influence the activity and cellular distribution of DAT, such that the fine-tuning of dopamine homeostasis occurs via a complex interplay of multiple signaling pathways.1234

DAT expression is regulated by:5

  • Transcription factors
  • Protein kinases
    • Protein Kinase A (PKA)
  • heterotrimeric G proteins
  • Bonding partner interactions
  • PKC or ERK
    • this is influenced by a number of neurotransmitter-receptor systems, e.g:3
      • Dopamine
      • Opioids
      • Glutamate
        There are functional interactions between DAT, D2-DA receptors and βγ-subunits of the G protein.

Structure of the DAT; C-terminus and N-terminus

The DAT consists of 12 transmembrane (TM) spanning helices. TMs 1, 3, 6 and 8 form the signal path for substrate permeation.
Uncoiled sections of TM1 and TM6 form the core of the active site and separate the helices into functional segments. Extracellular and intracellular gates above and below the active site determine inward and outward conformations and control the direction of dopamine movement. The DAT has large N- and C-terminal extensions (N-terminus and C-terminus) that project into the cytoplasm. The C- and N-termini have docking sites for post-translational modifications, interactions with binding partners and regulatory motifs.3 These can also be used to control the activity of the DAT.

The C-terminus (C-terminal region, carboxy-terminus) is the end of a protein/peptide molecule that contains the free carboxy group (formerly: carboxyl group; -COOH) that is not involved in a peptide bond. The N-terminus (N-terminal region, amino terminus) at the opposite end of the molecule contains the free amino group (-NH2) that is not involved in a peptide bond. Proteins are synthesized from the N-terminal end. Protein biosynthesis on the ribosome ends at the C-terminus. The last amino acid is determined by the last coding mRNA triplet before the stop codon. Thus, protein start and protein end are distinguishable. Since a carboxy group in a polypeptide is always linked to an α-terminal amino group of the following amino acid, an amino group remains free at the beginning of a polypeptide or protein and a carboxy group at the end.67

9.1.1.1. Changes in the number / activity of the DAT
9.1.1.1.1. Changes in DAT over the course of life

At birth, rats have 20-30% of the DAT they have at 14 to 60 days of age. By 104 weeks of age, DAT molecular mass continues to increase slightly. Similarly, N-linked glycosylation, which regulates DAT processing and targeting, is negligible at birth.8

In humans, adults have a significantly lower number of dopamine transporters in the striatum than children. For every 10 years of age, there is a decrease of 7 %, with the decrease being significantly higher up to around 40 years of age than thereafter. In 50-year-olds, the number of DATs is only about half as high as in 10-year-olds.910 (6% decrease from the age of 40)11
At the same time, the number of dopaminergic neurons decreases with age. The amount of phasically released and basal extracellular dopamine in the striatum remains the same.12

9.1.1.1.2. Up- and downregulation of the DAT

DAT are also regulated by extracellular dopamine levels. A reduction in dopamine synthesis decreased the density of DAT and its function in the striatum, while an increase in dopamine levels caused upregulation of DAT binding.13 Stimulation of D2-autoreceptors also leads to a downregulation of DAT in the striatum.14 This indicates a compensatory down- or upregulation of DAT as an adaptation to reduced or increased dopamine levels. Downregulation of DAT has also been observed in dopaminergic cells in the midbrain following the loss of dopamine synapses in the striatum.15

Important findings on the function of the DAT result from the observation of rodents without dopamine transporters. See also ⇒ DAT-KO mouse In the article ⇒ ADHD in animal models in the chapter ⇒ Neurological aspects.

Alpha-methyl-p-tyrosine also causes a downregulation of DAT in the striatum16

9.1.1.1.3. Dopamine transporter increased or decreased in ADHD?

While the question as to which DAT gene variant is more common in ADHD is regularly answered with “DAT 10R”, the statements as to whether the DAT number tends to be increased or decreased in ADHD are contradictory.
However, the Consequences seem to be partly identical.
A reduced DAT number/DAT activity leads to an increased extracellular dopamine level (tonic hyperdopaminergic) and a reduced phasic release due to insufficiently refilled vesicles, while an increased DAT number/DAT activity leads to a reduced extracellular dopamine level (tonic hyperdopaminergic), with simultaneously too high reuptake of the phasically released dopamine, which prevents its effect at the receptors (phasic hypodopaminergic). Both hypotheses conclusively explain a reduced phasic dopamineeffectivelevel (phasic hypodopaminergic).

9.1.1.1.3.1 Hypothesis 1: reduced DAT in ADHD (Consequences: extracellular hyperdopaminergic, phasic hypodopaminergic)

A meta-analysis of 9 studies concluded that people with ADHD who were medication-naïve had a 14% reduction in the number of DAT in the striatum, while previously medicated people with ADHD had an increased number of DAT compared to those who were not.17 However, the study appears to be subject to limitations with regard to the definition of medication naivety.18
A recent study also found a correlation between inactive DAT and ADHD, while an overactive DAT correlated with alcohol addiction.19

9.1.1.1.3.2 Hypothesis 2: increased DAT in ADHD (Consequences: extracellular and phasic hypodopaminergic)

Other sources report that the number of dopamine transporters in the striatum is increased by 70% in adults with ADHD compared to those who are not affected.20

One possible conclusion could be that increased DAT levels in ADHD lead to a reduction in synaptic and extra-synaptic = extracellular dopamine. It is also conceivable that an increase in DAT represents an adaptive upregulation response to compensate for an increased level of dopamine release.

In both cases, methylphenidate can normalize these values.21

9.1.1.1.3.3 Study situation: rather increased DAT (number/activity) in ADHD)

To date, the studies indicate that DAT are increased or more active in ADHD-HI (and possibly ADHD-C) than in ADHD-I. However, there are no reports of a reduced DAT count or activity in ADHD (compared to non-affected individuals). More on this under DAT differences between the subtypes In the article The subtypes of ADHD: ADHD-HI, ADHD-C (mixed type), ADHD-I (ADD), ADHD-RI (restricted inattentive) and others

9.1.1.2. D2 autoreceptors regulate DAT

Influence D2 autoreceptors
- the expression of DAT on the plasma membrane
- the activity of the DAT

D2 receptor agonists can reduce (in the caudate putamen) or increase (in the nucleus accumbens) DAT expression.22

Conversely, DAT expression can impair the function of the D2 autoreceptor. In DAT-KO mice, there is almost no D2 autoreceptor activity. Furthermore, the tissue dopamine content is greatly reduced in these mice, while dopamine metabolism is increased. In contrast, D2/- mice showed an unchanged tissue dopamine content and only slightly increased dopamine metabolism. The absence of D2 autoreceptors appears to barely affect dopamine synthesis and metabolism, while self-inhibition of dopamine release and reuptake is severely impaired 23

For more on the D2 autoreceptors, see below in this article.

9.1.1.3. Beta-phenylethylamine (PEA) influences DAT via TAAR1 (?) and D2 autoreceptors

Beta-phenylethylamine (PEA)24 and dopamine25 affected the function of DAT (Slc6A3) 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.26

9.1.1.4. Sodium influences DAT reuptake

Dopamine reuptake is dependent on sodium.27 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.28
Sodium substitution causes rapid hyperpolarization of the membrane, which decreases dopamine efflux.29 Reduced 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.

9.1.1.5. Phosphorylation influences DAT

Phosphorylation is catalyzed by different kinases at two different regions of the domain 3
Phosphorylation is enhanced by

  • Activation of protein kinase C (PKC)
  • AMP30
    • dependent on PKC
    • Kinase activation possibly due to drug-induced increase in cytosolic Ca2+ or reactive oxygen species
  • METH
    • dependent on PKC
    • Kinase activation possibly due to drug-induced increase in cytosolic Ca2+ or reactive oxygen species

Phosphorylation acts at the DAT-N terminus.

9.1.1.5.1. Protein kinase C (PKC) reduces DAT activity

PKC-mediated phosphorylation rapidly downregulates DAT capacity in several ways. PKC causes:

  • increased DAT endocytosis31
    • Trigger of DAT endocytosis is mediated by N-terminal ubiquitylation32
    • Forms of endocytotic regulation:33
      • short and acute
        • fast transportation to and from the surface
      • long-term
        • lysosomal degradation
    • DAT are recycled (after internalization in endosomes of the cell)
  • reduced transport capacity (Vmax)315
  • reduced rate of DAT plasma membrane recycling34
    • further increases the degree of DAT internalization
  • increased efflux35 via G(q)-coupled receptors36
    All these processes cause an increase in extracellular dopamine.3

DAT endocytosis (internalization, downregulation)
Endocytosis is actually the uptake of foreign material into the cell (internalization) by invaginating or constricting parts of the cell membrane to form vesicles or vacuoles. However, endocytosis also regulates the number of transporters and receptors on the cell membrane. Extensive activation of PKC triggers the lysosomal degradation of DAT.31
DAT endocytosis is mediated by clathrin5 and requires dynamin5, Flot137 and possibly Nedd4-2 (for38, against39.)
The internalized DAT colocalize with transferrin and are completely degraded in the endosomal/lysosomal pathway within 2 hours after activation of protein kinase C.4041

9.1.1.5.2. Extracellular signal-regulated kinases (ERK1 to ERK8) increase DAT activity

ERK (extracellular signal-regulated MAP kinase, ERK MAP kinase, extracellular signal-regulated kinases) belong to the mitogen-activated kinases (MAP kinases) and the serine/threonine kinases. ERKs regulate cell processes such as mitosis, meiosis, proliferation and cell differentiation. The ERKs are regulated by cell surface receptors.

ERK increase the DAT transport capacity.
ERK inhibitors reduce DAT expression and DAT dopamine uptake.3
ERK regulate DAT via dopamine and kappa-opioid receptors, which upregulate DAT dopamine uptake and DAT surface levels through ERK-dependent processes

ERK I/II activity was increased by taurine in the presence of AMPA or H2O2.42
Taurine showed a reduction in DAT dopamine uptake in SHR rats (an ADHD animal model), while low-dose taurine increased it43

9.1.1.5.3. Kappa-opiod receptors regulate DAT phosphorylation

KOR antagonists reduced the increased dopamine efflux in vivo in the human DAT gene variant VAL559 and normalized dopamine release. Similarly, the increased DAT-Thr53 phosphorylation and increased DAT trafficking in hDAT VAL559 was normalized. Conversely, wild-type KOR agonists increased DAT-Thr53 phosphorylation and DAT trafficking. hDAT VAL559 is associated with ADHD, ASD and BPD.44

9.1.1.6. Ubiquitination influences DAT

Ubiquitination (also: ubiquitylation) takes place via 3

  • Nedd4-2
  • Parkin

Ubiquitination acts at the DAT-N terminus.

9.1.1.6.1. Ubiquitination via Nedd4-2 influences DAT

Nedd4-2 causes monubiquitylation, which is enhanced by PKC activation (as a mechanism for stimulated endocytosis) 3

Nedd4-2- is required for DAT endocytosis triggered by PKC.38

9.1.1.6.2. Ubiquitination via Parkin influences DAT

Parkin binds to the C-terminus.45

Parkin is an E2-dependent E3 protein ubiquitin ligase:45

  • Protection against dopamine-induced alpha-synuclein-dependent cell toxicity in dopaminergic SK-N-SH cells
  • Impairment of alpha-synuclein/DAT coupling through interaction with the DAT-C terminus
  • Blockade of alpha-synuclein-induced increase in DAT cell surface expression and DAT dopamine uptake
9.1.1.7. Syntaxin 1A (Syn1A) increases DA uptake and reduces efflux

The plasma membrane protein syntaxin 1A regulates other proteins including neurotransmitter transporters. Syn1A binds the N-terminal amino acid residues 1-33.3

Syn1A increases DAT dopamine uptake and reduces DAT DA efflux.
Reduced Syn1A or reduced Syn1A-DAT binding causes

  • increased intake
  • increased channel activity
  • reduced efflux
  • reduced transporter phosphorylation

Syn1A also induces the release of neurotransmitters from the vesicles.
The combination of these abilities of Syn1A could serve the spatial or temporal coordination of neurotransmitter action.

9.1.1.8. S-palmitoylation increases DAT activity

Palmitoylation and phosphorylation regulate DAT reciprocally.

S-palmitoylation is the addition of a saturated fatty acyl group via a thioester bond 3
S-palmitoylation acts at the DAT C-terminus. A 16-carbon palmitate group reversibly modifies the DAT by means of a thioester bond46

Native and expressed dopamine transporters (DATs) are palmitoylated, which has several functions:47
Reinforced DAT palmitoylation

  • kinetically and acutely increases the DAT transport Vmax
    Inhibition of DAT palmitoylation
  • reduced the transport volume
    • without loss of DAT protein
    • without changing the DAT surface values
      persistent suppression of the palmitoylation of synaptosomes or cells caused
  • DAT protein losses
  • Production of DAT fragments
    which indicates regulation of DAT degradation by palmitoylation
9.1.1.9. Calcium-calmodulin-dependent protein kinase (CaMK) regulates DAT

CaMK binds to C-terminal amino acid residues 612-617 3
CaMK binds at the DAT-C terminus.

Binding of CaMKIIalpha (Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)) to the C-terminus of DAT appears to facilitate phosphorylation of the N-terminus of DAT and mediate amphetamine-induced DAT dopamine efflux.48
CaMKIIalpha

  • binds to the distal C-terminus of DAT
  • colocalizes with DAT in dopaminergic neurons
  • phosphorylates serine in the distal DAT-N terminus.
    • A mutation of these serines eliminated the stimulating effects of CaMKIIalpha.
  • A mutation of the C-terminus of DAT, which impairs CaMKIIalpha binding, also impaired amphetamine-induced DAT dopamine efflux
  • The CaMKII inhibitor KN93 reduced the amphetamine-induced DAT dopamine efflux-
9.1.1.10. α-Synuclein (α-Syn) increases DAT activity

Binds to amino acid residues 606-6203 of the C-terminus.4945

Alpha-synuclein binding to the C-terminus of the DAT is accelerated:4550

  • dAT dopamine reuptake
  • dopamine-induced cellular apoptosis
9.1.1.11. Flotillin 1 (Flot1) increases DAT-DA efflux

Flotillin-1/Reggie-2 (Flot1) is a membrane raft protein. Its binding sites on the DAT are unknown.
Flot137

  • is required to localize DAT
  • is required for PKC-regulated internalization (endocytosis) of the DAT
    • S315A mutation of Flot1 cannot induce DAT endocytosis
    • according to another opinion, Flot1 is not required for DAT endocytosis39
  • is essential for amphetamine-induced dopamine efflux in DAT
    • a deletion of Flot1 reduced the amphetamine-induced dopamine efflux
  • is not essential for dopamine (re)uptake
9.1.1.12. Regulating protein-protein interactions DAT

Direct protein-protein interactions through intracellular proteins such as:

  • α-Synuclein51
  • PICK151
  • Hic-551
  • Synaptogyrin-3 and VMAT252
    regulate the DAT function.
9.1.1.13. βγ-Subunits of the G protein inhibit DAT activity

βγ-subunits of G-proteins are intracellular signaling molecules that regulate a variety of physiological processes through interactions with enzymes and ion channels.
Gβγ subunits regulate DAT activity via a direct interaction between the intracellular carboxy-terminus of DAT and Gβγ.
Overexpression of the Gβγ subunit or the Gβγ activator mSIRK caused a rapid inhibition of DAT activity in heterologous systems. Gβγ activation by mSIRK also inhibited dopamine uptake in brain synaptosomes and dopamine clearance from the striatum.4

9.1.1.14. Synaptogyrin-3 increases DAT activity

The synaptic vesicle protein synaptogyrin-3 and DAT are colocalized at presynaptic striatal terminals. Synaptogyrin-3 interacts with the N-terminus of DAT. The expression of synaptogyrin-3 correlated with DAT activity

  • in PC12 and MN9D cells
  • not in the non-neuronal HEK-293 cells
    The VMAT2 inhibitor reserpine abolishes the effect of synaptogyrin-3 on DAT activity.52
9.1.1.15. Membrane rafts influence DAT activity

Membrane rafts are small (10-200 nm), heterogeneous, highly dynamic domains enriched with sterols (e.g. cholesterol) and sphingolipids that compartmentalize cellular processes (such as receptor signaling through segregation of specific protein populations). Small rafts can sometimes be stabilized by protein-protein and protein-lipid interactions to form larger platforms.53
DATs are fairly evenly distributed between membrane raft and non-raft domains.
Raft distribution significantly influences DAT regulation. Rafts are the primary locations:3

  • of PKC-stimulated DAT phosphorylation
  • interaction with Flot1
  • the interaction with Syn1A
  • interaction with Rin1
  • pKC-stimulated endocytosis (unclear)
    Incorrect targeting of DAT could therefore affect the processes that depend on it, such as
  • Efflux
  • Down regulation
    The alignment of DAT with Raft
  • correlates with the cholesterol content of the membrane
  • requires Flot1
    • Flot1 is a protein that organizes palmitoylated membrane raft
  • causes lower lateral membrane mobility of the DAT
9.1.1.16. Cholesterol increases DAT activity

Cholesterol is required for

  • DA transport activity54
  • AMPH-stimulated efflux54
  • PKC-stimulated downregulation of the DAT
  • Changes in the DAT conformational equilibrium.
    Cholesterol deficiency can therefore reduce DAT activity (uptake and efflux).
    Cholesterol chelation reduces the affinity of DAT for dopamine.55, without altering DAT efflux or uptake rate.56

The aforementioned processes influenced by cholesterol are involved in DAT phosphorylation and interaction with binding partners, which is partly attributed to DAT localization in the membrane raft3 and partly to the presence of raft-independent mechanisms.
Cholesterol interacts with many proteins via Cholesterol Recognition Amino Acid Consensus (CRAC) motifs (sequence; L/V-X(1-5)-Y-X(1-5)-K/R). These bind sterol via hydrophobic, aromatic and H-bonding interactions. DAT contains six CRAC motifs of which it is not known whether they are functional.
Whether an interaction of DAT with cholesterol via these motifs contributes to the raft partitioning of DAT3 is unclear.54

9.1.1.17. Cannabinoids inhibit dopamine reuptake

Cannabinoids inhibit the reuptake of57
- Adenosine (stronger)
- Dopamine (weaker)
in the striatum. This applies to a large number of endogenous and exogenous cannabinoid ligands. The maximum strength of reuptake inhibition often corresponded to that of the dopamine reuptake inhibitor GBR12783 and the equilibrative nucleoside reuptake inhibitor dipyridamole. The inhibition was apparently not through the cannabinoid-1 receptor.

9.1.1.18. N-glycans increase DAT activity

The DAT is a glycoprotein with three N-glycosylation sites in the second extracellular loop.
Blockade of DAT-N glycosylation reduced DAT at the surface as well as intracellularly. However, glycosylation does not appear to be essential for DAT expression. Non-glycosylated DAT were less stable at the surface and showed significantly increased endocytosis. Non-glycosylated DAT did not transport dopamine as efficiently as wild-type DAT. Blockade of N-glycosylation enhanced the efficacy of cocaine-like drugs in inhibiting dopamine uptake. Non-glycosylated DAT at the cell surface showed significantly reduced catalytic activity and altered sensitivity to reuptake inhibitors compared to wild-type.58
Glycosylation of the DAT correlates with the susceptibility of dopaminergic cells in the midbrain in Parkinson’s disease.59

A small study was conducted on ADHD:60

  • reduced di-/triantennary N-glycans with bisecting N-acetylglucosamine (GlcNAc)
  • increased antennal fucosylation
  • a reduced α2-3-sialylation
9.1.1.19. DHEA blocks dopamine uptake in striatal synaptosomes

DHEA blocks dopamine uptake in striatal synaptosomes 6162

9.1.1.20. DAT gene variants

A number of DAT gene polymorphisms are known. These can strongly influence the activity and other behavior of the DAT.
For more information see SLC6A3, DAT1, dopamine transporter gene (chromosome 5p15.3; 10-R allele, VNTR) In the article Genes as genetic candidates for ADHD with a plausible pathway to ADHD

9.1.1.21. Early childhood enriched environment reduces DAT in the mPFC

Early childhood enriched environment caused a 35% reduction in maximum dopamine reuptake in rats with a 39% reduction in DAT expression in the mPFC (compared to rats reared under depleted conditions). No differences were found in nucleus accumbens or striatum.63

9.1.1.22. DAT regulation through autophagy

Autophagy may modulate the reuptake of dopamine by selective degradation of DAT.64
The following causal chain is described:

  • A malfunction of the lysosomal autophagy causes
  • reduced DAT degradation, thereby
  • higher number of active DAT
  • high dopamine reuptake
  • low extracellular / high intracellular dopamine
  • excessively high cytoplasmic dopamine levels
  • high dopamine oxidation processes
  • oxidative stress
  • Neurodegeneration
9.1.1.23. Nurr1 and Pitx3 activate DAT promoter transcription

Nurr1 and Pitx3 cooperatively activate the transcription of DAT promoter sequences65
Murine and human DAT promoter sequences contain neighboring Nurr1 and Pitx3 binding sites within the proximal DAT promoter.

9.1.1.24. DAT regulation through epigenetics

DAT expression is influenced by epigenetic modulation (e.g. histone acetylation and DNA methylation):66 Unfortunately, the sources cited by Wu et al for the following information did not consistently reflect the presentation and could therefore not be verified. The statements should therefore be viewed with caution.

Histone acetylation:

  • Unlike most housekeeping genes, the DAT promoter does not have a TATA box. This makes the DAT particularly susceptible to epigenetic interference. Therefore, the initiation of DAT transcription might strongly depend on the formation of the TATA-box-binding protein (TBP). TBP is primarily regulated by histone acetylation.67
  • Valproate, an HDAC inhibitor, can increase DAT mRNA and protein levels in human SK-N-AS cells.
  • Administration of DNMT inhibitors slightly increased DAT mRNA levels in human neuroblastoma cells. HDACs increased DAT expression in human neuroblastoma cells more strongly.
  • Ontogeny studies on DAT mRNA from postnatal day 0 to day 182 showed significantly increased H3K9/K14 acetylation in the DAT promoter during this period. Meanwhile, binding of Nuclear Receptor-Related 1 protein (Nurr1) and Paired Like Homeodomain 3 (Pitx3) to the DAT promoter was also increased in an age-related manner.

DNA methylation:

  • The DNA methylation of the DAT promoter increases with age.

9.1.2. D2 autoreceptors

Extracellular dopamine docks onto presynaptic D2 autoreceptors. These inhibit

  • direct
    • Dopamine release (especially in the striatum and PFC)68
    • Excitability of dopamine neurons69
      through
    • Opening K+ channels
    • Closing of Ca2+ channels.70
      • Stimulation of DRD2 increases the intracellular Ca2+ concentration and activates Ca2+/calmodulin-dependent protein kinase II71
      • CaMKII enhances the DAT dopamine efflux induced by AMP48
  • indirectly through downstream regulation69
    • the expression of tyrosine hydroxylase
      • slow, long-lasting mechanism
      • Downregulation of tyrosine hydroxylase after prolonged autoreceptor activation causes
        • reduced filling of the presynaptic dopamine vesicles72
          • Quinpirole, a D2 receptor agonist, inhibits TH activity and reduces the quantum size of K+-evoked releases by 40 to 50 %
          • L-DOPA increases DA synthesis and quantitative size in DA cells independent of TH and prevents the effect of quinpirole on the quantitative size of DA
        • The D2 effect on quantal size reduction is likely mediated by reduced TH affinity for its cofactor tetrahydropbiopterin (BH4) by blocking a cAMP-dependent signaling pathway that mediates TH phosphorylation
      • altered distribution and expression of the vesicular monoamine transporter (VMAT)
    • the expression of DAT on the plasma membrane
    • the activity of the DAT
      • inhibition of dopamine release feedback in a matter of seconds

Spatial arrangement of autoreceptors69

  • Axonal autoreceptors control the synthesis, release and uptake of dopamine.
  • Midbrain autoreceptors mediate the transmission that controls the firing of dopamine neurons.
  • Soma autoreceptors reduce the firing rate of dopaminergic neurons

As a result, D2 receptor agonists inhibit dopamine release and dopamine signaling in vivo, while D2 receptor antagonists enhance it.69 However, D2 antagonists do not alter the release of evoked endogenous dopamine if the release is triggered by a single stimulus. Apparently, even tonic background dopamine firing is not sufficient to increase extracellular dopamine to the point where D2 autoreceptors activate DAT regulation. D2 autoreceptors appear to accelerate DAT dopamine uptake only during excessive activation or during prolonged stimulation cycles.73 Prolonged dopamine interstimulus intervals (5-30 sec) were not regulated by D2 autoreceptor activation 23
Thus, D2-mediated autoinhibition of dopamine release involved only phasic dopamine bursts of intervals less than 5 seconds, was greatest ∼500 msec after stimulation, and persisted for up to 5 seconds 23

D2 autoreceptors keep the phasic dopamine signal clean and constant.

D2 autoreceptors produced higher (constant) amplitudes of the main signal in a burst of 5 PPD signals and prevent the dopamine signal from resonating, so that the main signals are easier to distinguish from the non-signal (cf. Schmitz et al. 2002 Figure 7).23
In a burst signal series, D2 autoreceptors prevent the amplitude peaks of the main signal from increasing further and further. When the D2 autoreceptors of wild-type mice were inhibited by the D2 antagonist sulpiride, the amplitude of the individual signal in a signal series of 10 PPD signals continued to increase until it almost doubled.23 This only occurred with signals in the sub-second range (here: 20 Hz), not with signals every second. A slight increase was observed as early as the second pulse, indicating an (albeit incomplete) onset of the effect of D2 autoreceptors on dopamine release within 50 ms.
The D2 auto-inhibition was23

  • maximum
    • between 150 and 300 ms after stimulation in vivo
    • 500 ms after stimulation in vitro
  • lasted
    • ∼600 ms in vivo
    • up to 5 seconds in vitro

Mesocortical VTA dopamine neurons projecting to the prefrontal cortex have lower levels of D2 receptors and GIRK channels and are therefore not subject to D2 autoreceptor-mediated dopamine inhibition.7475

While both D2 and D3 receptors are present on dopamine neurons, the D3 receptor probably plays only a minor functional role as an autoreceptor. The majority of autofeedback inhibition is likely to be mediated by the D2 receptor.69 No D3 autoreceptors are found on nigrostriatal dopamine neurons (in the dorsal striatum) 23
While D2Long may predominate in heteroreceptors, both D2Short and D2Long may serve as autoreceptors on dopamine neurons.69

Whether D2 autoreceptors have a significantly higher affinity for dopamine than heteroreceptors is at least questionable. Instead, a large number of D2 autoreceptors in the striatum could also be the reason why even low concentrations of dopamine agonists cause an inhibition of dopamine release.69

D2 autoreceptors primarily regulate the exocytotic release of dopamine from axon terminals. Released dopamine activates the autoreceptors, which reduces the probability of dopamine release upon subsequent presynaptic stimulation. The inhibition triggered by S2 autoreceptors lasts between a few hundred milliseconds and several seconds.

Selective D2 antagonists do not measurably increase the extracellular DA in the mPFC because it is immediately reabsorbed by NET. In inactivated NET, the D2 antagonist racloprid showed an increase in extracellular DA in the mPFC.68

D2 autoreceptors influence the DAT in a sex-specific manner.76

9.1.3. Dopamine rocker PFC / striatum

9.1.3.1. Low tonic dopamine = high (“disinhibited”) phasic dopamine in the striatum

Heinz hypothesizes that a reduced (glutamatergic-mediated) tonic dopamine release in the striatum correlates with a disinhibited phasic dopamine release.77 Thus, dopamine deficiency in the PFC leads, among other things, to an increased response of mesolimbic dopaminergic neurons to stress.78

Abnormally low tonic extracellular dopamine leads to upregulation of the autoreceptors so that the stimulation-induced phasic dopamine is increased. High phasic dopamine is thought to explain the high sensitivity of people with ADHD to external stimuli. Stimuli that cause moderate excitation of the brain result in good performance, while stimuli that are too weak or too strong impair cognitive performance. Strong stimuli can easily disrupt attention, while a low-stimulus environment causes low arousal, which is typically compensated for by hyperactivity.
The authors also report on stochastic resonance. Stochastic resonance means that moderate noise facilitates stimulus discrimination and cognitive performance. Computational modeling showed that more noise is required in ADHD for stochastic resonance to occur in dopamine-deficient neural systems. This prediction is supported by empirical data.7980

Under acute stress, the dopamine levels of the PFC and striatum appear to diverge. Rats showed a twofold increase in dopamine in the PFC during electric shocks, while it only increased by 25 % in the striatum and 39 % in the nucleus accumbens.81 Another study found reduced dopamine levels in the striatum, slightly reduced dopamine levels in the PFC, unchanged dopamine levels in the nucleus accumbens and ventral tegmentum and reduced dopamine levels in the ventrolateral midbrain after repeated stress.82

Just as cocaine or amphetamine administration (as a drug, not as a medication) causes sensitization to subsequent stress responses, repeated stress can also increase the subsequent response to cocaine. This sensitization does not occur in animals that cannot secrete glucocorticoids due to removal of the adrenal gland, so it could be mediated by stress-induced increased glucocorticoid secretion.8384858687

9.1.3.2. High tonic dopamine = low phasic dopamine in the striatum

Normally, a high extracellular dopamine level leads to the downregulation of phasic dopamine responses triggered by stimuli via autoreceptors.79 Thus, tonic (extracellular) dopamine in the striatum inhibits phasic dopamine release by activating D2 autoreceptors. The D2 autoreceptors are activated by means of:88

  • Dopamine release into the extracellular space due to stimulation of glutamate receptors near the autoreceptors
  • Diffusion of dopamine from the synaptic cleft after phasic release into the extracellular space
    • The activation of the inhibitory dopamine autoreceptors by dopamine diffusion from the synaptic cleft into the extracellular space represents a self-inhibiting feedback loop

9.1.4. Extracellular dopamine activates phasic dopamine in the PFC

In the PFC, on the other hand, (extracellular) dopamine is thought to promote the phasic release of dopamine, in that high extracellular dopamine increases and prolongs the activation of the pyramidal cells. This correlates with a low significance of the inhibitory D2 autoreceptors in the PFC.88

9.1.5. Dopamine regulation directly at terminals

The release of dopamine can also be controlled locally at the terminals themselves. It is possible that the dynamics of dopamine release associated with reward value encoding are largely regulated by local control, while at the same time dopamine cell firing provides important reward prediction error-like signals for learning.89 Direct control of DA at terminals may yield spatiotemporal DA patterns that are independent of cell body spines.

9.1.5.1. Amygdala regulates dopamine directly at terminals

The basolateral amygdala can directly influence dopamine release in the nucleus accumbens, even when the VTA is inactivated.90 Inactivation of the basolateral amygdala reduces dopamine release in the nucleus accumbens and thus the corresponding motivated behavior, independent of dopaminergic firing by the VTA.91

9.1.5.2. Glutamate, acetylcholine, opioids regulate dopamine directly at terminals

Dopamine terminals have neurotransmitter receptors for

  • Glutamate
  • Opioids
  • Acetylcholine
    • Activation of cholinergic interneurons increases phasic dopamine in the striatum9293
    • NMDAR antagonists have an acute effect94
      • increase tonic dopamine
      • reduce phasic (burst) firing9596
    • NMDAR agonists on the VTA have an acute effect94
      • increased phasic firing in the nucleus accumbens97

9.1.6. D3 receptors reduce extracellular dopamine in the mPFC

D3 receptor agonists reduced DA release and extracellular DA levels in the mPFC/PFC.98

9.1.7. D1 receptors reduce extracellular dopamine in the mPFC

D1 receptor agonists99 such as apomorphine100 reduced DA release and extracellular DA levels in the mPFC.

9.1.8. D2 heteroreceptors regulate dopamine in the striatum

Studies in autoDrd2KO mice showed that not only D2 autoreceptors but also D2 heteroreceptors (i.e. D2 receptors on non-dopamine neurons) are involved in dopamine regulation. This D2 heteroreceptor-mediated mechanism acts more strongly on neurons in the SNc projecting to the dorsal striatum DSt than on neurons in the VTA projecting to the NAc nucleus (DA spillover DSt: 37 %, NAc nucleus: 59 %, both compared to wild-type mice). D2R signaling thus appears to differentially regulate mesolimbic and nigrostriatal mediated functions101

9.1.9. N-glycans and DRD2, DRD3

DRD2 is subject to N-glycosylation. N-glycans at the N-terminus of DRD2 suppress the internalization of the receptor into the cytosol, as they are essential for the interaction with caveolin-1. Caveolin-1 inhibits endocytosis. N-glycans are involved in the desensitization and expression of DRD3 on the cell surface and in its clathrin-dependent internalization.102

9.1.10. BDNF regulates dopamine in the striatum

This presentation is based on Sulzer et al 72

The neurotrophic factor BDNF acts on TrkB (and P75) receptors.
Genetic elimination (BDNF-/- mice) or strong reduction of BDNF (BDNF-/+ mice) in the brain causes103104

  • evoked dopamine release
    • significantly reduced in the NAc shell
    • significantly reduced in the dorsal striatum
    • unchanged in the NAc core
  • dramatically increased consumption of high-fat food (intake of normal food unchanged)
  • normalized consumption of high-fat food due to D1 receptor agonists
  • extracellular dopamine levels in the caudate nucleus / putamen more than doubled
  • increased increase in dopamine levels after potassium stimulation (120 mM) (10-fold) compared to wild-type controls (6-fold)
  • electrically evoked dopamine release as well as the dopamine uptake rate in the caudate nucleus / putamen reduced

BDNF administration

  • increases the DA overflow in the striatum evoked by depolarization
  • can partially restore electrically evoked dopamine in BDNF-/+ mice
  • leaves extracellular dopamine levels unchanged

9.1.11. GDNF regulates dopamine release and dopamine uptake in the striatum

This presentation is based on Sulzer et al 72

The neurotrophic factor GDNF can regulate striatal DA release and uptake. GDNF plays a key role in the development, maintenance and regeneration of the mesostriatal DA system.105
In vivo, GDNF injection into the NAc caused an increase in K+-triggered DA release in the caudate nucleus/putamen106 via a long-lasting increase in TH phosphorylation and presumably DA synthesis in the striatum and SNc107
GDNF increases the amount of DA released from vesicles in axonal varicosities of midbrain DA neurons.108
GDNF increases the number of DA neurons in the midbrain and terminals in the striatum, thereby increasing dopamine in the striatum.109
GDNF regulates DAT surface expression via its receptor (Ret) by means of the guanine nucleotide exchange factor protein VAV2 (from the Rho family). Mice lacking Vav2 or Ret show increased DAT activity in the NAc.109

9.1.12. Insulin regulates dopamine in striatum, VTA, substantia nigra

This presentation is based on Sulzer et al 72

Insulin in the brain mainly originates peripherally from β-cells of the pancreas.
Insulin receptors are widely expressed in the brain. They are found

  • in the striatum
    • particularly frequently in the NAc
  • on DA neurons in VTA and substantia nigra pars compacta
  • on cholinergic interneurons

Insulin regulates dopamine:110

  • in the striatum
    • increased DAT dopamine (re)uptake
      • via PI3 kinase
    • increased DA release
      • through insulin receptors on cholinergic interneurons111
      • requires activation of nicotinic acetylcholine receptors (nAChR)
        • nAChR antagonists block insulin action
        • Choline acetyltransferase knockout mice show no effect of insulin on dopamine
      • stronger than DAT recovery increase
    • in sum, increased extracellular (?) dopamine111
  • in the VTA112
    • increased DAT dopamine (re)uptake
    • overall reduced extracellular dopamine, as there is no increased DA release
    • Endocannabinoids enhance reduction of extracellular dopamine in the VTA by inducing long-term depression of VTA neurons113114
  • in the substantia nigra115
  • increased firing rate in half of the dopaminergic SNc neurons
  • not in mice expressing insulin receptors in tyrosine hydroxylase (TH)-expressing neurons

In addition to the satiety signal, insulin also seems to be able to trigger a (dopaminergic) reward signal111

  • Behavioral tests on taste preference in behaving animals show that insulin in the NAc bowl influences food preference
  • Insulin could be involved in food-related learning

9.1.13. Substance P regulates dopamine in the striatum

This presentation is based on Sulzer et al 72

Substance P binds to neurokinin-1 receptors expressed by DA neurons
In the striatum, substance P is released by D1R-expressing neurons and accumulates in striatal compartments, the so-called striosomes.
Substance P modulates DA release depending on the position of the striosome matrix

  • within the striosomes, the DA transmission is intensified
  • dA transmission is reduced at the striosome-matrix boundaries
  • it is unchanged in the surrounding matrix (Figure 4A)

The regulation of DA release by the accumulation of other modulators and receptors, including mu opioid receptors, between striosomes and matrix compartment is not yet known, but may represent a very important process in the regulation of DA release and basal ganglia function.

9.2. Regulatory mechanisms according to neurotransmitters / hormones etc.

9.2.1. Dopamine - Dopamine autoregulation

9.2.1.2. D2 autoreceptors inhibit phasic dopamine

For D2 autoreceptors, see above in this article.

9.2.1.3. Dopamine rocker PFC / striatum
9.2.1.3.1. Low tonic dopamine = high (“disinhibited”) phasic dopamine in the striatum

Heinz hypothesizes that a reduced (glutamatergic-mediated) tonic dopamine release in the striatum correlates with a disinhibited phasic dopamine release.77 Thus, dopamine deficiency in the PFC leads, among other things, to an increased response of mesolimbic dopaminergic neurons to stress.78

Abnormally low tonic extracellular dopamine leads to upregulation of the autoreceptors so that the stimulation-induced phasic dopamine is increased. High phasic dopamine is thought to explain the high sensitivity of people with ADHD to external stimuli. Stimuli that cause moderate excitation of the brain result in good performance, while stimuli that are too weak or too strong impair cognitive performance. Strong stimuli can easily disrupt attention, while a low-stimulus environment causes low arousal, which is typically compensated for by hyperactivity.
The authors also report on stochastic resonance. Stochastic resonance means that moderate noise facilitates stimulus discrimination and cognitive performance. Computational modeling showed that more noise is required in ADHD for stochastic resonance to occur in dopamine-deficient neural systems. This prediction is supported by empirical data.7980

Under acute stress, the dopamine levels of the PFC and striatum appear to diverge. Rats showed a twofold increase in dopamine in the PFC during electric shocks, while it only increased by 25 % in the striatum and by 39 % in the nucleus accumbens.81 Another study found reduced dopamine levels in the striatum, slightly reduced dopamine levels in the PFC, unchanged dopamine levels in the nucleus accumbens and ventral tegmentum and reduced dopamine levels in the ventrolateral midbrain after repeated stress.82

Just as cocaine or amphetamine administration (as a drug, not as a medication) causes sensitization to subsequent stress responses, repeated stress can also increase the subsequent response to cocaine. This sensitization does not occur in animals that cannot secrete glucocorticoids due to removal of the adrenal gland, so it could be mediated by stress-induced increased glucocorticoid secretion.8384858687

9.2.1.3.2. High tonic dopamine = low phasic dopamine in the striatum

Normally, a high extracellular dopamine level leads to the downregulation of phasic dopamine responses triggered by stimuli via autoreceptors.79 Thus, tonic (extracellular) dopamine in the striatum inhibits phasic dopamine release by activating D2 autoreceptors. The D2 autoreceptors are activated by means of:88

  • Dopamine release into the extracellular space due to stimulation of glutamate receptors near the autoreceptors
  • Diffusion of dopamine from the synaptic cleft after phasic release into the extracellular space
    • The activation of the inhibitory dopamine autoreceptors by dopamine diffusion from the synaptic cleft into the extracellular space represents a self-inhibiting feedback loop
9.2.1.4. E-DA activates phasic DA in the PFC

In the PFC, on the other hand, (extracellular) dopamine is thought to promote the phasic release of dopamine, in that high extracellular dopamine increases and prolongs the activation of the pyramidal cells. This correlates with a low significance of the inhibitory D2 autoreceptors in the PFC.88

9.2.1.5. DA regulation directly at terminals

Dopamine release may also be controlled locally at the terminals themselves, resulting in spatiotemporal dopamine patterns that are independent of cell body spiking. It is possible that the dynamics of dopamine release associated with reward value encoding are largely regulated by local control, while at the same time dopamine cell firing provides important reward prediction error-like signals for learning89

9.2.1.5.1. Amygdala regulates DA directly at terminals

The basolateral amygdala can directly influence dopamine release in the nucleus accumbens, even when the VTA is inactivated.90 Inactivation of the basolateral amygdala reduces DA release in the nucleus accumbens and thus the corresponding motivated behavior, independent of dopaminergic firing by the VTA.91

9.2.1.5.2. Glutamate, acetylcholine, opioids regulate DA directly at terminals

Dopamine terminals have neurotransmitter receptors for

  • Glutamate
  • Acetylcholine
    • rapid control of dopamine release in the striatum9293
  • Opioids
9.2.1.6. D3 receptors reduce e-DA in the mPFC

D3 receptor agonists reduced DA release and extracellular DA levels in the mPFC/PFC.98

9.2.1.7. D1 receptors reduce e-DA in the mPFC

D1 receptor agonists99 such as apomorphine100 reduced DA release and extracellular DA levels in the mPFC.

9.2.2. Noradrenaline

9.2.2.1. E-NE influences DA recording and e-DA

Since DAT are rare in the PFC and DA in the PFC is primarily reabsorbed by NET, DA and NE compete in the PFC for reuptake by NET.
From this, it was hypothesized that high extracellular NE would decrease DA uptake, leading to increased extracellular DA. Conversely, low extracellular NE would facilitate DA uptake, leading to decreased extracellular DA levels.
In addition, α2-adrenergic autoreceptors are thought to influence the levels of NE and DA, in part by controlling catecholamine release from dopaminergic terminals, so that their blockade and stimulation would lead to an increase and decrease of DA in the PFC, respectively.

In contrast to these hypotheses, extracellular DA in the PFC appears to be derived not only from dopaminergic but also from noradrenergic terminals, where DA acts as both a precursor and a co-transmitter of NE. Fittingly, central noradrenergic denervation prevented the α2-adrenoceptor antagonist atipamezole-induced increase in extracellular DA in the mPFC, suggesting that noradrenergic terminals are the primary source of α2-adrenoceptor antagonist-induced DA release in the mPFC.68

9.2.2.2. α2-Adrenergic autoreceptors inhibit DA in the PFC

α2-adrenergic autoreceptors inhibit the release of dopamine in the PFC.68

9.2.2.3. α2-Adrenoceptors inhibit DA in the nucleus accumbens

The nucleus accumbens receives considerable noradrenergic input.116117 This input inhibits the release of dopamine via α2-adrenoceptors.118119
The noradrenergic system therefore influences the dopaminergic system in the nucleus accumbens116, which can influence ADHD symptoms.

9.2.3. Glutamate

Glutamate increases tonic dopamine in the striatum

In the case of dopamine, phasic release is thought to occur due to incoming action potentials, while tonic release is triggered by glutamatergic signals from the PFC to the striatum.120121122 However, tonic dopamine release in the striatum only occurs when glutamate levels are unusually high. However, the same lead author confirmed in another study that glutamate has an influence on the tonic dopamine increase in the striatum caused by dopamine reuptake inhibitors. Glutamate antagonists reduced the effect of the dopamine increase caused by dopamine reuptake inhibitors.123124

A selective mGlu5R agonist inhibits the motor activation induced by D2R agonists. mGlu5R antagonists, on the other hand, cancel out the effect of D2R antagonists. A2AR and mGlu5R agonists reinforce each other, as do A2AR and mGlu5R receptor antagonists. These interactions form the basis for the use of A2AR antagonists (and possibly also mGlu5R antagonists) in Parkinson’s disease.125

Signals from the laterodorsal tegmental nucleus (part of the brainstem) trigger phasic dopamine responses in the VTA, which in turn increase the extrasynaptic (basal/tonic) dopamine release in the nucleus accumbens (part of the striatum), among others, with activation of glutamate receptors in the ventral tegmentum (VTA), which downregulates the signals from the laterodorsal tegmental nucleus. Thus, a high basal/tonic dopamine level in the nucleus accumbens leads to a reduced phasic dopamine release. A D2 receptor agonist reduced the glutamatergic-mediated signaling decrease from the laterodorsal tegmental nucleus, so that phasic dopamine increased again and tonic dopamine decreased. A high basal/tonic dopamine level can thus inhibit the phasic doopamine release controlled by the laterodorsal tegmental nucleus. Glutamate receptors act as autoreceptors in the VTA, which help to stabilize the reduced phasic dopamine level when tonic dopamine is high. The interaction between autoreceptors in the VTA and D2 autoreceptors, e.g. in the striatum, controls the functional balance between tonic and phasic dopamine.126

9.2.3.1 Nitric oxide increases tonic dopamine in the striatum via glutamate

Furthermore, nitric oxide appears to increase dopamine levels in the striatum by increasing glutamatergic tone.127

To what extent there are connections here with the elevated nitric oxide blood plasma levels in ADHD, which are further increased by MPH,128 is an interesting question.

9.2.4. Nicotine

9.2.4.1. Nicotine increases phasic DA in the striatum

Nicotine is a β2 nicotinic receptor agonist and increases the phasic release of dopamine in the striatum129

9.2.4.2. Dihydro-β-erythroidine (DHβE) inhibits phasic DA in the striatum

Dihydro-β-erythroidine (DHβE) is a plant-derived competitive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2 units (β2* NAChRs; β2 nicotinic receptors). DHβE reduces the phasic release of dopamine in the dorsolateral striatum129
Consequences are that reward anticipation, which is controlled by phasic dopamine in the striatum and even more so in the nucleus accumbens, is also increased by β2-nicotinic receptor agonists - such as nicotine - .

9.2.4.3. Ovarian hormones influence dopamine release in the NAc via α4β2*-nAChRs

Dopamine release from axon terminals in the NAc is rapidly modulated by local regulatory microcircuits independent of somatic activity in the VTA. Tonic (slow and regular) and phasic (short, burst/spike) dopamine release around NAc is subject to strong modulation by cholinergic (ChAT) interneurons. The ChAT signal via α4β2*-containing nicotinic acetylcholine receptors (nAChRs), which are located directly at dopamine terminals.
ChAT regulation of dopamine release by nAChRs is fundamentally different in men and women.
In female mice, ChAT regulation of dopamine release by α4β2*-nAChRs is mostly absent. Impaired nAChR modulation of dopamine release was not affected by the estrus cycle in intact (non-ovariectomized) females. However, impaired nAChR modulation of dopamine release was restored in ovariectomized females. 17β-Estradiol (E2) acutely increased dopamine release, which was blocked by α4β2*-NAChRs antagonists. Females showed a lesser effect of nAChR agonists on dopamine release, which would be expected with desensitized receptors. In behavioral studies, male mice learned faster than intact females when ChAT interneurons were activated.
Independent of the hormonal cycle, circulating ovarian hormones influence the ability of α4β2*-nAChRs on dopamine terminals to modulate dopamine release in the NAc. This suggests that sex-specific differences in ChAT regulation of dopamine neurotransmission underlie sex-dependent differentiation in reward learning.130

9.2.5. Acetylcholine

9.2.5.1. Acetylcholine increases phasic dopamine in the striatum

Acetylcholine is a β2 nicotinic receptor agonist and influences the release of dopamine in the striatum.131

9.2.5.2. Acetylcholine activates dopaminergic neurons in VTA

Acetylcholine activates dopaminergic neurons of the VTA.132
Cholinergic brainstem neurons via activation of nicotinic and muscarinic M5 receptors. This causes:

  • increased dopamine bursts in VTA
  • Influencing reward processes/addiction

9.2.6. TAAR1 inhibits dopamine

TAAR1 (Trace Amine 1 Receptor) influences the regulation of dopamine. VTA and substantia nigra show a high expression of TAAR1.133

TAAR1 agonists reduce the firing rate of dopaminergic neurons in the VTA.134135
Inhibition of TAAR1 enhances dopaminergic activity.135

More on this in the article =&gt Traceamine.

9.2.7. Adenosine inhibits dopamine

Adenosine receptors are found everywhere in the brain in the vicinity of dopamine receptors and are closely linked to them (sometimes even as heteromers). Adenosine inhibits dopamine, adenosine antagonists such as caffeine (coffee, cola, black tea) or theobromine (cocoa) therefore increase dopamine.
More on this in the article =&gt Adenosine.

9.2.8. Stimulants

9.2.8.1. Methylphenidate

Methylphenidate increases extracellular dopamine; phasic only dependent on D2 receptors

Methylphenidate appears to increase tonic dopamine. Phasic dopamine is not altered by MPH, apparently because the D2 receptor feedback mechanism inhibits it. If a D2 antagonist is given in parallel with MPH, MPH also increases phasic dopamine.136 In our view, this raises the question of the extent to which the amount and binding sensitivity of the available D2 receptors leads to an individually different effect of MPH in persons with ADHD.

9.2.8.2. Amphetamine increases phasic dopamine

Amphetamine increases dopamine in various ways:137

9.2.8.2.1. Amphetamine increases phasic DA through reuptake inhibition

AMP inhibits dopamine reuptake138139 140 which increases tonic dopamine release.138

9.2.8.2.2. Amphetamine increases (short)-phase dopamine through increased release
  • AMP promotes the phasic burst firing of dopamine neurons
    • Via alpha-1-adrenoceptors141 and
    • By reducing the inhibitory glumatergic transmission142
  • AMP induced upregulation of dopamine release from the vesicles 143
  • AMP caused a dose-dependent increase in dopamine release in response to phasic electrical impulses138
  • AMP increased the amplitude, duration and frequency of spontaneous dopamine transients (the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine).138
  • Low-dose AMP increased dopamine transients evoked by anticipated reward138
  • AMP reverses the direction of the dopamine transporter (dopamine efflux)144145137
    • Causes non-exocytotic release, independent of the action potential
    • Limited by vesicular exhaustion

Amphetamine appears to primarily increase phasic dopamine at drug-relevant doses. At doses far above drug-relevant doses, AMP appears to cause a paradoxical increase in tonic and phasic dopamine:143

In anesthetized rats137

  • In the dorsal striatum
    • 1 mg/kg amphetamine (this corresponds to a very high drug dose)
      • A slight increase in short-phase dopamine by approx. 15%
      • A significant reduction in long-phase dopamine by approx. 40%
      • A very strong reduction of the tonic dopamine by approx. 65 %
    • 10 mg/kg amphetamine in the dorsal striatum (this corresponds to a drug dose)
      • An extreme increase in short-phase dopamine by approx. 300 %
      • A reduction of the long-phase dopamine by approx. 20%
      • A very strong reduction of the tonic dopamine by approx. 75%
    • 40 mg/kg cocaine in the dorsal striatum (this corresponds to a drug dose)
      • An extreme increase in short-phase dopamine by approx. 300 %
      • No change in the long-phase dopamine
      • No change in the tonic dopamine
  • In the ventral striatum
    • 1 mg/kg amphetamine (this corresponds to a very high drug dose)
      • A significant increase in short-phase dopamine by approx. 50%
      • A slight increase in the mid-phase dopamine
      • A slight reduction in long-phase dopamine
    • 10 mg/kg amphetamine in the dorsal striatum (this corresponds to a drug dose)
      • An extreme increase in short-phase dopamine by approx. 370 %
      • An increase in the mid-phase dopamine by approx. 40%
      • No change in the long-phase dopamine
    • 40 mg/kg cocaine in the dorsal striatum (this corresponds to a drug dose)
      • A strong increase in short-phase dopamine by approx. 170 %
      • A slight increase in the mid-phase dopamine
      • A slight reduction in long-phase dopamine

Short-phase dopamine refers to the dopamine released in response to 0.4 seconds of electrical stimulation, which addresses the readily releasable pool of vesicles.
Mid-phase dopamine refers to the dopamine released in response to 2 seconds of electrical stimulation.
Long-phase dopamine refers to the dopamine released in response to 10 seconds of electrical stimulation, which is fed from the reserve vesicle pool.
Tonic dopamine, on the other hand, is increased by amphetamine through a reversal of the dopamine transporters (dopamine efflux).137
The authors interpret the results to mean that amphetamine has different effects on different vesicle pools that store the phasic dopamine in the presynapse.

The extent to which amphetamine also increases phasic dopamine at normal to low doses within the usual drug range remains to be seen.

Vesicles are typified in:146

  • Readily Releasable Pool
    • Primarily positioned in the presynaptic zone
    • Usually ready for immediate distribution
  • Recycling pool
    • Is addressed by moderate stimulation
    • Is continuously replenished
  • Reserve Pool
    • Is only addressed by exceptionally intensive stimulation
    • Not involved in normal physiological reaction
9.2.8.3. AMP releases dopamine in PFC via NET

Amphetamine releases extracellular dopamine in the PFC primarily via the NET, while methamphetamine barely seems to target the NET.147

9.2.9. Casein kinase 2 (CK2) regulates dopamine

Mice without CK2 showed hyperactive behavior mediated by altered dopamine action.148

9.2.10. Cellular prion protein (PrP(C)) regulates dopamine

Cellular prion protein (PrP(C)) is widely distributed in the brain. It may regulate neuroplasticity in the brain via the glutamatergic and serotonergic systems. PrP(C) is colocalized with dopaminergic neurons and synapses in the striatum.
A genetic deletion of PrP(C) caused149

  • in the striatum
    • Downregulation of dopamine D1 receptors
    • Downregulation of DARPP-32
  • in the PFC
    • reduced dopamine levels

(PrP(C)) appears to influence149

  • Dopamine synthesis
  • Dopamine levels
  • Dopamine receptor density
  • Signaling pathways in different brain regions

9.2.11. Oestrogen and oestradiol promote dopamine in the striatum and PFC

Estrogen acts in the striatum and nucleus accumbens via a G-protein-coupled membrane estrogen receptor (GPER) to rapidly and directly increase dopamine release and dopaminergic-mediated behaviors - but not in male rats.150

There is a close connection between oestrogen and increased dopamine activity in reward structures in the brain.151152
The effect of oestrogen on dopamine activity and reward motivation also appears to be influenced by the binding of oestradiol to membrane-bound oestrogen receptors, particularly in the striatum. The sex-dependent effect could result from a sex-dependent unequal distribution of the receptors.153154155

During the luteal phase (which is characterized by high estradiol and progesterone concentrations), a greater availability of D2 binding sites in the striatum was reported.156 This was concluded to be due to reduced dopamine release during the high estradiol phase.157

Estrogen levels influence mesolimbic dopaminergic activity (release, uptake and transport) in a cycle-dependent manner.158
The basal dopamine level in the PFC is higher in rodents:159

  • highest during estrus (fertile phase, corresponding to the end of the follicular phase / proliferation phase with ovulation in humans, which is accompanied by a very high estrogen level)
  • is at its lowest during dioestrus (corresponding to the middle of the secretory phase to the beginning of the proliferation phase in humans, infertile period)
  • lowest during proestrus, the phase in which estrogen levels are typically highest (corresponding to the second half of the proliferation phase in humans)

However, this probably only correlates to a limited extent with the fact that some women with ADHD require higher doses of ADHD medication immediately before the menstrual phase, i.e. at the end of the luteal phase, than in other cycle phases.160 Although oestrogen levels fall during this time, the lowest oestrogen levels are found during menstruation (1st to 4th day of the cycle) and in the first days of the proliferative phase (5th to 14th day of the cycle). There are no reports of a cycle-related increased need for ADHD medication during these periods.
The intensification of PMS symptoms at the end of the luteal phase could be due to the serotonin-increasing effect of oestrogen, which ceases during this phase, causing a drop in serotonin.161

Estrogen modulates dopamine and norepinephrine in the PFC. 20 μg/kg 17β-estradiol induced in rodents:162163

  • improved memory consolidation
  • increased dopaminergic, noradrenergic and serotonergic neurotransmission in the PFC
  • increased concentrations of 5-HT, MHPG (metabolite of NE)
  • increased DOPAC (metabolite of DA)
  • increased turnover rate of NE to MHPG shortly after treatment

Estrogen controls dopamine levels by influencing dopamine degradation in the PFC through COMT.162 See under Oestrogen reduces COMT and thus dopamine degradation by COMT in the PFC In the section Regulation of COMT in the article Dopamine reuptake, dopamine degradation

Oestradiol also promotes the release of dopamine.164165166
Progesterone, on the other hand, reduces dopaminergic activity in women with addiction disorders.166
In the striatum, estradiol rapidly modulates dopamine release by binding to membrane-bound estradiol receptors.167155

9.2.12. Melanin-concentrating hormone (MCH) inhibits dopamine

This section is largely based on Torterolo et al (2016).168

The MCH and dopamine systems interact to control behavioral states.169
The neuropeptide melanin-concentrating hormone (MCH) is synthesized in the hypothalamus. MCH-ergic neurons project throughout the CNS, including to the dopaminergic areas substantia nigra and VTA. MCH expression differs by sex. MCH expression depends on the female reproductive state. MCH controls energy homeostasis and promotes sleep.
MCH neurons fire

  • strongest during REM sleep
  • agent during non-REM sleep
  • weak when awake

MCH-ergic fibers and receptors are found in the dopaminergic mesocorticolimbic system, which is a key center for activation and motivation.
MCH induces sleep. MCH inhibits dopamine release, which causes upregulation of dopamine receptors.

There are 2 MCH receptors:

  • MCHR1
    • is expressed together with dopamine receptors in the nucleus accumbens shell. It is possible that MCH and dopamine interact in the nucleus accumbens shell during motivated responses such as food or drug seeking.
      • MCH alone did not alter spike firing in the nucleus accumbens shell in vitro
      • MCH together with D1 or D2 agonists increased the firing rate
      • MCH blocked dopamine-induced phosphorylation of the AMPA glutamate receptor in the nucleus accumbens shell.
  • MCHR2

MCH has a primarily inhibitory effect both presynaptically and postsynaptically. Presynaptically, it reduces the release of GABA and glutamate.

Conversely, dopamine influences the MCH system.
Dopamine hyperpolarizes MCH-ergic neurons via the activation of noradrenergic alpha-2a receptors
MCH neurons receive more GABAergic inputs than glutamatergic inputs. Dopamine influences these inputs in a complex way.
Dopamine reduces the excitability of MCHergic neurons. D1 or D2 agonists in the hypothalamus did not affect MCH gene expression.
Parkinson’s disease, which is characterized by severe dopamine deficiency, is associated with increased MCH concentrations, which may be responsible for the impairment of REM sleep in Parkinson’s disease. Excess MCH is also observed in depression. MCHR1 antagonists could be helpful in the treatment of depression.
Obesity correlates with an excess of MCH. In contrast, an increase in dopamine (due to ADHD medication) is often associated with a loss of appetite. MCH and dopamine appear to play a complementary role in eating behavior and thus obesity, just as is discussed for other behaviors.

9.2.13. CHR activates dopaminergic neurons in VTA

CRH activates dopaminergic neurons of the VTA.132
CRH receptors were found in 70 % of the dopaminergic VTA cells. CRF receptor 2 was more strongly expressed than CRF receptor 1.170

9.2.14. Substance P activates dopaminergic nerve cells in VTA

Substance P activates most of the dopaminergic neurons of the VTA.170

9.2.15. Neuropeptide Y activates dopaminergic neurons in VTA

Neuropeptide Y activates only a part of the dopaminergic and GABAergic neurons of the VTA.170

9.2.16. Orexin (hypocretin) activates dopaminergic neurons in VTA

Orexin (hypocretin) increases mean firing rate and bursting in dopaminergic neurons of the VTA as well as in neighboring GABAergic neurons.132

9.2.17. Neuropeptides without activation of dopaminergic neurons in VTA

Alpha-melanocyte-stimulating hormone had no effects on dopaminergic cells of the VTA and affected only a small proportion of GABAergic neurons. Ghrelin, agouti-related peptide, cocaine, amphetamine-related transcript (CART) and leptin did not modulate the firing rate and membrane potential of VTA neurons.170

9.2.18. Cortisol inhibits dopamine synthesis

Glucocorticoid receptors are found on numerous dopaminergic cells in the midbrain and hypothalamus.171 It is assumed that cortisol can influence the release of dopamine in the basal ganglia and in nigrostriatal and mesolimbic pathways.172
Cortisol inhibits tyrosine hydroxylase, an enzyme that limits catecholamine synthesis by acting as a catalyst for the conversion of tyrosine to DOPA. Tyrosine hydroxylase is inhibited by cortisol (as well as by dopamine and noradrenaline themselves (negative feedback).173
A retrospective analysis found a correlation between the use of inhaled corticosteroids in younger children with moderate to severe asthma. This correlation was not found in older children.174

9.2.19. β-Arrestin inhibits the effect of dopamine

DA receptors can also be activated by mechanisms independent of G proteins. This may be mediated by the multifunctional adaptor protein arrestin, which binds DA receptors phosphorylated by GPCR kinases (GRKs) and recruits several proteins, including Akt, GSK-3, MAPK, c-Src, Mdm2 and N-ethylmaleimide-sensitive factor. Binding of arrestin to active phosphorylated receptors stops further activation of G-proteins and promotes endocytosis of the receptor. There are seven GRKs in mammals: GRK2, GRK3, GRK4, GRK5 and GRK6 regulate D1R and D2R, while GRK4 controls the D3R. In the striatum, GRKs 2, 3, 5 and 6 are expressed with different expression levels and different cellular and subcellular distribution.175176

β-Arrestin:177

  • causes desensitization of receptors
  • causes internalization of receptors
  • serves as a multifunctional signal transmitter
    • β-Arrestin serves as an adaptor/scaffold to connect the activated receptors with various signaling pathways within the cell178
    • β-Arrestin (like cAMP) appears to influence D1 agonists in a dose-dependent manner

9.2.20. VMAT2 blockade prevents dopamine transmission

Dopamine transmission is deactivated by blocking or switching off the vesicular monoamine transporter type 2 (VMAT2) 179180

9.2.21. Botulinum A and B impair dopamine transmission

Botulinum toxins A and B cleave SNAP-25 and synaptobrevin-2 respectively. Synaptobrevin-2 is found in the dopamine varicosities.181

9.2.22. Alcohol consumption increases dopamine

The consumption of alcohol increases dopamine182

9.2.23. Carbohydrates increase dopamine

Carbohydrate consumption (fast food) increases dopamine.182

9.2.24. Lack of food influences dopamine

Changes in chronic food availability promote the desensitization of D2 receptors in the midbrain.183
Chronic light food restriction increases dopaminergic burst firing in the substantia nigra. The increased burst firing persisted even after 10 days of free feeding following chronic food restriction.
A single day of fasting did not affect the burst firing.

9.2.25. GABA inhibits dopamine

GABA, which binds to GABA-B receptors, inhibits the release of dopamine in the VTA. 18223 VTA dopamine addresses the nucleus accumbens.

9.2.26. FOXP2HUM influences dopamine levels in the brain

A substitution of two amino acids (T303N, N325S) in the transcription factor FOXP2 showed reduced dopamine levels in mice:184

  • Nucleus accumbens
  • Frontal cortex
  • Cerebellum
  • Putamen caudatus
  • Globus pallidus
  • Glutamate, GABA, serotonin unchanged

In contrast, increased dopamine levels were found in heterozygous FOXP2wt/ko mice, which have an intermediate FOVP2 protein level and thus serve as a model of reduced FOXP2 expression.

Since FOXP2 is not expressed in dopaminergic cells, this is an indirect effect on dopamine levels.

9.2.27. REV-ERB-Alpha

Rev-Erbα (nuclear receptor subfamily 1 group D member 1) is a circadian nuclear receptor.185
Rev-Erbα inhibits the transcription-translation feedback loop (TTFL) of the suprachiasmatic nucleus, which targets Bmal1 mRNA.
Rev-Erbα affects midbrain dopamine production by suppressing tyrosine hydroxylase mRNA production. Tyrosine hydroxylase levels were highest at night, while Rev-Erbα levels were lowest. This suggests an inverse relationship.
Rev-Erbα-KO mice show higher DA release in the nucleus accumbens.

9.2.28. Oxytocin

Activation of oxytocin neurons in the VTA increases dopaminergic activity in the mesocorticolimbic system. Mice showed a decrease in dopaminergic release in the nucleus accumbens after administration of an oxytocin receptor agonist.186

9.2.29. RACK1

RACK1 is a small, versatile scaffold protein that interacts with many receptors and signaling molecules. In dopamine neurons, RACK1 binds to DAT and regulates DAT phosphorylation by protein kinase C.187

9.2.30. Nf-kB

The expression of the striatal dopamine D2 receptor (DRD2) and the adenosine A2A receptor (A2AAR) is regulated by the nuclear factor kappaB (NF-kappaB, Nf-kB). NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:188

  • more A2AAR
  • less A1AR
  • less DRD2 mRNA
  • reduced [(3)H]-methylspiperone bond
  • increased G(alphaolf) and G(alphas) proteins
    • these transmit A2AAR signals
      -reduced G(alphai1) protein
      this forwards signals from A1AR and DRD2

Nf-kB p50-KO mice showed increased locomotor activity in response to caffeine.

9.2.31. Steroid hormones influence dopamine

All substrates and metabolites of 5α-reductase metabolism influence dopamine transmission and signaling in a variety of ways:189

  • Pregnenolone
  • Progesterone
  • 5α-DHP
  • Allopregnanolone
9.2.31.1. DHEA promotes tonic and phasic dopamine release in the striatum

Dehydroepiandrosterone (DHEA) appears to increase tonic and phasic dopamine release in the striatum.62190
The extracellular dopamine concentration was increased with DHEA administration, while dopamine metabolites and the dopamine/metabolite ratio were decreased. DHEA also decreased motor activity, especially in the first 20 minutes after treatment.
An earlier study by the same lead author found that DHEA reduced dopamine turnover (by up to 33%) in the striatum (but not in the nucleus accumbens) and increased serotonin turnover (by up to 76%) in both regions.191 The reduced dopamine release reported there was no longer maintained in the more recent study.

9.2.31.2. Allopregnanolone

Antagonist: Isoallopregnanolone
Similar substances: brexanolone, ganaxolone, zuranolone

The neurosteroid allopregnanolone

  • reduces the evoked dopamine release depending on sex and estrus phase192
  • inhibits basal and stress-induced dopamine release in the PFC and nucleus accumbens.193
  • increases dopamine release and the dopaminergic response to morphine in the nucleus accumbens194

Acute stress increases and chronic stress reduces neurosteroid synthesis.189

5α-reductase is involved in the synthesis of allopregnanolone189
More on this at Allopregnanolone In the chapter Neurological aspects.
5α-reductase inhibitors could therefore influence the dopamine system, but have significant and long-lasting side effects.

9.2.31.3. Pregnenolone

Pregnenolone

  • modulates the release of dopamine in the PFC of rodents189
  • it cures schizophrenia-like behavioral phenotypes in a dose-dependent manner in dopamine transporter (DAT) knockout mice195
  • Pregnenolone administration significantly alleviates hyperdopaminergic behavioral phenotypes caused by deletion of DAT in the brain:189
    • psychomotor agitation
    • Stereotypy
    • cognitive deficits
      • for prepulse inhibition (PPI)
      • in the object recognition test (ORT)196, Wong et al., 2012)
    • improves the functional capacity of patients with schizophrenia compared to placebo
      • but without significant improvement in cognitive symptoms197
    • attenuates the phenomena caused by Δ9-tetrahydrocannabinol (THC) of198196
      • strong increase in extracellular dopamine levels in the NAC
      • increased firing activity of the VTA neurons
    • reverses psychosis-like states in rodents through endogenous allosteric negative modulation of the CB1 receptor199

9.2.32. Extracellular calcium influences dopamine release in the striatum and midbrain

Extracellular calcium is equally necessary for the release of dopamine:200

  • Axon terminations in the striatum
  • Dendrites in the midbrain

9.2.33. Type input / type depletion

Tyrosine is a precursor of dopamine.
An administration of tyrosine can increase dopamine in the brain, a depletion of tyrosine can reduce dopamine. More on this under Tyrosine for ADHD

9.2.34. Serotonin inhibits dopamine

5-HT neurons innervate dopamine neurons both in the regions of dopamine synthesis (VTA and SNc) and in the dopaminergic target regions (nucleus accumbens, mPFC and amygdala). The influence of serotonin on dopaminergic signaling is dependent on:201
- Subtype of the 5-HT receptor (e.g. 5-HT1a, 5-HT1b, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7)
- the DA target (VTA or substantia nigra)
- reciprocal afferent/efferent connections
5-HT agonists/agonists, SSRIs and 5-HT lesions influence the activity of dopamine neurons in a very complex and as yet incompletely understood way.202

Serotonin inhibits dopamine.

  • Serotonin administration inhibits the firing of dopaminergic neurons203
    • in VTA (weak)
      • e.g. through injected SSRIs204
    • in substantia nigra pars compacta (stronger)
    • in the nucleus accumbens by injected 5-HT2/2B serotonin antagonists, but not by 5-HT2A/2C antagonists205
  • Electrical stimulation of the dorsal raphe nucleus206, primarily by 5-HT-1A agonists, only weakly by 5-HT-1B agonists207
    • in substantia nigra pars compacta
      • Inhibition of dopaminergic neurons with low firing rate
      • Excitation of other neurons
    • in VTA
      • Inhibition of dopaminergic neurons that project into the nucleus accumbens
      • Excitation of other VTA-DA neurons
  • Stimulation of 5-HT terminals caused (only with simultaneous glutamate release202 and modulated by GABA.208
    • in VTA smaller excitatory postsynaptic potentials
    • in SNc larger excitatory postsynaptic potentials
  • 5-HT2C antagonists increase dopamine in the nucleus accumbens
    • Amitriptyline (10 mg, but not 5 mg) and mianserin (5 mg, but not 2.5 mg) injected
      • significantly increased extracellular dopamine in the nucleus accumbens209
      • Mianserin also improved anhedonia symptoms of chronic mild stress210
      • D2/D3 antagonists blocked this improvement202

Dopamine contributes to the development of depression via the meslombic dopamine pathway,211

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