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8. Regulation of dopamine

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8. Regulation of dopamine

Dopamine is moderated by a variety of regulatory mechanisms. The following is the beginning of a collection of these factors and is by far incomplete.

8.1. Dopamine - Dopamine Regulation

8.1.1. D2 autoreceptors inhibit phasic dopamine

Extracellular dopamine (mostly from tonic release) docks onto presynaptic D2 autoreceptors. These inhibit (especially in the striatum and PFC) dopamine release.1

Selective D2 antagonists therefore do not measurably increase extracellular DA in mPFC because this is promptly resumed by NET. In inactivated NET, the D2 antagonist racloprid showed an increase in extracellular DA in mPFC.1

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

Heinz hypothesizes that reduced (glutamatergic-mediated) tonic dopamine release in the striatum correlates with disinhibited phasic dopamine release.2 Thus, dopamine deficiency in the PFC leads to, among other things, an increased response of mesolimbic dopaminergic neurons to stress.3

Abnormally low tonic extracellular dopamine leads to upregulation of autoreceptors so that stimulus-induced phasic dopamine is amplified. High phasic dopamine is thereby thought to explain the high sensitivity of affected individuals to external stimuli. Stimuli that produce moderate brain arousal cause good performance, whereas stimuli that are too low or too strong impair cognitive performance. Strong stimuli can easily disrupt attention, while a low-stimulus environment causes low arousal, which is typically compensated by hyperactivity.
The authors further report on stochastic resonance. Stochastic resonance means that moderate noise facilitates stimulus discrimination and cognitive performance. Computational modeling showed that in ADHD, more noise is required for stochastic resonance to occur in dopamine-deficient neural systems. This prediction was supported by empirical data, he said.45

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 increased by only 25% in the striatum and 39% in the nucleus accumbens.6 Another study found decreased dopamine levels in the striatum, slightly decreased dopamine levels in the PFC, unchanged dopamine levels in the nucleus accumbens and ventral tegmentum, and decreased dopamine levels in the ventrolateral midbrain after repeated stress.7

Just as cocaine or amphetamine administration (as a drug, not a medication) causes sensitization to subsequent stress responses, repeated stress can also increase subsequent responses to cocaine. This sensitization does not occur in animals that cannot secrete glucocorticoids because of adrenal gland removal, so it could be mediated by stress-induced increased glucocorticoid secretion.89101112

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

Normally, high extracellular dopamine levels lead to downregulation of phasic dopamine responses triggered by stimuli via autoreceptors.4 Thus, tonic (extracellular) dopamine in the striatum inhibits phasic dopamine release by activating D2 autoreceptors. The D2 autoreceptors are activated by means of:13

  • Dopamine release into the extracellular space due to stimulation of glutamate receptors in the vicinity of autoreceptors
  • Diffusion of dopamine from the synaptic cleft after phasic release into the extracellular space
    • Activation of inhibitory dopamine autoreceptors by dopamine diffusion from the synaptic cleft into the extracellular space constitutes a self-inhibitory feedback loop

8.1.4. E-DA activates phasic DA in the PFC

In contrast, in the PFC, (extracellular) dopamine is thought to promote phasic dopamine release by increasing and prolonging high extracellular dopamine activation of pyramidal cells. This correlates with a minor role of inhibitory D2 autoreceptors in the PFC.13

8.1.5. DA regulation directly at terminals

The release of dopamine may also be controlled locally at the terminals themselves. It is possible that the dynamics of dopamine release associated with reward encoding are largely regulated by local control, while at the same time dopamine cell firing provides important reward prediction error-like signals for learning.14 Direct control of DA at terminals may yield spatiotemporal DA patterns that are independent of cell body spines

8.1.5.1. Amygdala regulates DA directly at terminals

The basolateral amygdala can directly influence dopamine release in the nucleus accumbens, even with the VTA inactivated.15 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.16

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

Dopamine terminals have neurotransmitter receptors for

  • Glutamate
  • Acetylcholine
    • via this, rapid control of dopamine release in the striatum1718
  • Opioids

8.1.6. D3 receptors reduce e-DA in the mPFC

D3 receptor agonists reduced DA release and extracellular DA levels in mPFC/PFC.19

8.1.7. D1 receptors reduce e-DA in the mPFC

D1 receptor agonists20 such as apomorphine21 reduced DA release and extracellular DA levels in mPFC.

8.2. Norepinephrine

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

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

In contrast to these hypotheses, extracellular DA in the PFC appears to derive not only from dopaminergic but also from noradrenergic terminals, where DA functions both as a precursor and as a co-transmitter of NE. Fittingly, central noradrenergic denervation prevented the increase in extracellular DA in the mPFC triggered by the α2-adrenoceptor antagonist atipamezole, suggesting that noradrenergic terminals are the primary source of DA released by α2-adrenoceptor antagonists in the mPFC.1

8.2.2. α2-Adrenergic autoreceptors inhibit DA in the PFC

α2-Adrenergic autoreceptors inhibit dopamine release in the PFC.1

8.3. Glutamate

Glutamate increases tonic dopamine in the striatum

In dopamine, phasic release is thought to occur due to incoming action potentials, whereas tonic release is triggered by glutamatergic signals from the PFC to the striatum.222324 However, tonic dopamine release in the striatum occurred only when glutamate levels were unusually high, he said. Meanwhile, the same lead author confirmed in another study that glutamate had an effect on tonic dopamine enhancement in the striatum by dopamine reuptake inhibitors. Glutamate antagonists reduced the effect of dopamine elevation by dopamine reuptake inhibitors.2526

A selective mGlu5R agonist inhibits motor activation induced by D2R agonists. mGlu5R antagonists, on the other hand, abolish 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 mGlu5R antagonists) in PD.27

Signals from the laterodorsal tegmental nucleus (part of the brainstem) trigger phasic dopamine responses in the VTA, which in turn increase 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 signals from the laterodorsal tegmental nucleus. Thus, high basal/tonic dopamine levels in the nucleus accumbens lead to decreased phasic dopamine output. A D2 receptor agonist reduced glutamatergic-mediated signal reduction from the laterodorsal tegmental nucleus, so that phasic dopamine increased again and tonic dopamine decreased. Thus, high basal/tonic dopamine levels may inhibit phasic doopamine release controlled by the laterodorsal tegmental nucleus. Glutamate receptors act as autoreceptors in the VTA, helping to stabilize decreased phasic dopamine levels when tonic dopamine is high. The interplay between autoreceptors in the VTA and D2 autoreceptors, e.g., in the striatum, controls the functional balance between tonic and phasic dopamine.28

8.3.1 Nitric oxide increases tonic dopamine in the striatum via glutamate

Further, nitric oxide in the striatum appears to increase dopamine levels by increasing glutamatergic tone.29

To what extent there are connections here with the elevated nitric oxide blood plasma levels in ADHD, which are further increased by MPH,30 is an interesting question.

8.4. Nicotine

8.4.1. Nicotine increases phasic DA in the striatum

Nicotine is a β2-nicotinic receptor agonist and increases phasic dopamine release in the striatum.31

8.4.2. 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 decreases phasic dopamine release in the dorsolateral striatum.31
It follows 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 .

8.5. Acetylcholine

8.5.1. Acetylcholine increases phasic dopamine in the striatum

Acetylcholine is a β2-nicotinic receptor agonist and affects dopamine release in the striatum.32

8.5.2. Acetylcholine activates dopaminergic neurons in VTA

Acetylcholine activates dopaminergic neurons of the VTA.33
Cholinergic brainstem neurons via activation of nicotinic and muscarinic M5 receptors. This causes:

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

8.6. TAAR1 inhibits dopamine

The TAAR1 (Trace Amine 1 Receptor) influences the regulation of dopamine. VTA and substantia nigra show high expression of TAAR1.34

TAAR1 agonists decrease the firing rate of dopaminergic neurons in the VTA.3536
Inhibition of TAAR1 enhances dopaminergic activity.36

More about this in the article =&gt Traceamine.

8.7. Adenosine inhibits dopamine

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

8.8. Stimulants

8.8.1. Methylphenidate

Methylphenidate increases extracellular dopamine; phasic only in response to D2 receptors

Methylphenidate appears to raise tonic dopamine. Phasic dopamine is not altered by MPH, apparently because the D2 receptor feedback mechanism inhibits this. If a D2 antagonist is given in parallel with MPH, MPH also increases phasic dopamine.37 In our view, this raises the question of the extent to which the amount and binding sensitivity of available D2 receptors in affected individuals results in an individually different effect of MPH.

8.8.2. Amphetamine increases phasic dopamine by release from vesicles and by reuptake inhibition

Amphetamine increases dopamine in several ways:38

8.8.3. Amphetamine increases phasic DA through reuptake inhibition

AMP inhibits dopamine reuptake3940 41 which increases tonic dopamine release.39

8.8.4. Amphetamine increases (short-)phasic dopamine through increased release

  • AMP promotes phasic burst firing of dopamine neurons
    • Via alpha-1 adrenoceptors42 and
    • By reducing the inhibitory glumatergic transmission43
  • AMP caused upregulation of dopamine release from vesicles 44
  • AMP induced increased dopamine release in response to phasic electrical impulses in a dose-dependent manner39
  • AMP increased the amplitude, duration, and frequency of spontaneous dopamine transients (the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine).39
  • Low-dose AMP increased dopamine transients elicited by anticipated reward39
  • AMP reverses direction of dopamine transporter (dopamine efflux)454638
    • Causes non-exocytotic release, independent of the action potential
    • Limited by vesicular depletion

Amphetamine appears to increase primarily 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:44

On anesthetized rats induced38

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

Short-phase dopamine means the dopamine released in response to 0.4 seconds of electrical stimulation, which addresses the readily releasable vesicle pool.
Mid-phase dopamine means the dopamine released in response to an electrical stimulation of 2 seconds.
Long-phase dopamine means 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 dopamine transporters (dopamine efflux).38
The authors interpret the results to mean that amphetamine has different effects on different vesicle pools that hold phasic dopamine in the presynapse.

It is open to what extent amphetamine also increases phasic dopamine at normal to low doses within the usual drug range.

Vesicles are typed in:47

  • Readily Releasable Pool
    • Primarily positioned in the presynaptic zone
    • Mostly ready for immediate distribution
  • Recycling Pool
    • Is addressed by moderate stimulations
    • Is continuously replenished
  • Reserve pool
    • Is addressed only by exceptionally intense stimulation
    • Not involved in normal physiological response

8.8.5. AMP releases dopamine in PFC via NET

Amphetamine releases extracellular dopamine in the PFC primarily via NET, whereas methamphetamine appears to barely target the NET.48

8.9. Casein kinase 2 (CK2) regulates dopamine

Mice lacking CK2 exhibited hyperactive behavior mediated by altered dopamine action.49

8.10. 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 by means of the glutamatergic and serotonergic systems. PrP(C) is colocalized with dopaminergic neurons and synapses in the striatum
A genetic deletion of PrP(C) caused50

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

(PrP(C)) appears to affect:50

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

8.11. Cannabinoids inhibit dopamine reuptake

Cannabinoids inhibit the reuptake of51
- Adenosine (stronger)
- Dopamine (weaker)
in the striatum. This involved a large number of both endogenous and exogenous cannabinoid ligands. The maximal strength of reuptake inhibition was often equivalent to that of the dopamine reuptake inhibitor GBR12783 and the equilibrative nucleoside reuptake inhibitor dipyridamole. Inhibition did not appear to be through the cannabinoid-1 receptor.

8.12. Estrogen promotes dopamine in the striatum

Estrogen has a rapid and direct enhancing effect on dopamine release and dopaminergic-mediated behaviors in striatum and nucleus accumbens via a G-protein-coupled membrane estrogen receptor (GPER) - but not in male rats.52
This correlates with the fact that some women with ADHD require higher doses of ADHD medications immediately before the menstrual phase, during the part of the cycle that correlates with the lowest estrogen levels, than during other phases of the cycle.

8.13. Melanin-concentrating hormone (MCH) inhibits dopamine

So far, this section is largely based on Torterolo et al (2016).53

The MCH and dopamine systems interact with respect to the control of behavioral states.54
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 female reproductive state. MCH controls energy homeostasis and promotes sleep
MCH neurons fire

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

8.14. CHR activates dopaminergic neurons in VTA

CRH activates dopaminergic neurons of the VTA.33
CRH receptors were found in 70% of dopaminergic VTA cells. CRF receptor 2 was more abundant than CRF receptor 2.55

8.15. Substance P activates dopaminergic neurons in VTA

Substance P activates most of the dopaminergic neurons of the VTA.55

8.16. Neuropeptide Y activates dopaminergic neurons in VTA

Neuropeptide Y activates only part of the dopaminergic and GABAergic neurons of the VTA.55

8.17. 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.33

8.18. Neuropeptides without activation of dopaminergic neurons in VTA

Alpha-melanocyte-stimulating hormone had no effect on dopaminergic cells of the VTA and affected only a small fraction 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.55

8.19. Cortisol inhibits dopamine synthesis

Glucocorticoid receptors are located on numerous dopaminergic cells of the midbrain and hypothalamus.56 Cortisol is thought to influence dopamine release in the basal ganglia and in nigrostriatal and mesolimbic pathways.57
Cortisol inhibits tyrosine hydroxylase, an enzyme that limits catecholamine synthesis by serving as a catalyst for the conversion of tyrosine to DOPA. Tyrosine hydroxylase is inhibited by cortisol (as well as by dopamine and norepinephrine themselves (negative feedback).58
A retrospective analysis found a correlation between inhaled corticosteroid use in younger children with moderate to severe asthma. This correlation was not found in older children.59

8.20. Arrestin inhibits dopamine action

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-sensing factor. Binding of arrestin to active phosphorylated receptors halts further activation of G proteins and promotes endocytosis of the receptor. In mammals, there are seven GRKs: GRK2, GRK3, GRK4, GRK5, and GRK6 regulate D1R and D2R, while GRK4 controls D3R. In the striatum, GRKs 2, 3, 5, and 6 are expressed with different expression levels and different cellular and subcellular distribution.6061

8.21. VMAT2 blockade inhibits dopamine transmission

Dopamine transmission is disabled by blocking or knocking out the vesicular monoamine transporter type 2 (VMAT2).6263

8.22. Botulinum A and B impair dopamine transmission

Botulinum toxins A and B cleave SNAP-25 and synaptobrevin-2, respectively. Synaptobrevin-2 is found in dopamine varicosities.64

8.23. β-Arrestin influences dopamine transmission

β-arrestin:65

  • causes desensitization of receptors
  • causes internalization of receptors
  • serves as a multifunctional signal transmitter
    • β-Arrestin serves as an adaptor/scaffold to connect activated receptors to various signaling pathways within the cell66
    • β-Arrestin (like cAMP) appears to affect D1 agonists in a dose-dependent manner

8.24. Protein kinase C (PKC) inhibits DAT

Protein kinase C (PKC) mediates the phosphorylation of the DAT protein. PKC induces inhibition of DAT in the form of membrane fusions, resulting in sequestration and internalization of the transporter proteins.
Phosphorylation mediated by PKC:67

  • stimulates clathrin- and dynamin-mediated endocytosis. This removes the DAT from the surface of the plasma membrane. This removal of DAT reduces their surface expression and thus the overall transport capacity, even at high substrate concentrations
  • reduces the functional kinetics of DAT molecules independent of a trafficking process
    • faster form of DAT inhibition
    • probably works in connection with membrane trafficking

Forms of endocytotic regulation:68

  • short and acute
    • fast transport to and from the surface
  • long-term
    • lysosomal degradation

Trigger DAT endocytosis:69

  • N-terminal ubiquitylation mediates PKC-stimulated endocytosis

Moreover, independent of endocytosis, the DAT protein itself can be inhibited without altering its expression levels at the plasma membrane.

8.25. 16-Carbon palmitate group increases DAT capacity

A 16-carbon palmitate group reversibly modifies DAT via a thioester bond.70 Enhanced DAT palmitoylation kinetically and acutely increases DAT transport Vmax. Sustained suppression of palmitoylation leads to targeted DAT degradation. Palmitoylation and phosphorylation reciprocally regulate DAT.

8.26. Protein-protein interactions regulate DAT

Direct protein-protein interactions through intracellular proteins such as:71

  • α-Synuclein
  • PICK1
  • Hic-5

regulate the DAT function.

8.27. Early childhood enriched environment reduces DAT in mPFC

Early childhood enriched environment caused a 35% decrease in maximal dopamine reuptake in rats with a 39% decrease in DAT expression in the mPFC (compared with rats reared in depleted conditions). No differences were found in nucleus accumbens or striatum.72

8.28. Changes in DAT expression

DAT expression can be regulated by:67

  • Transcription factors
  • Protein kinases
    • Protein Kinase A (PKA)
  • heterotrimeric G proteins
  • Binding partner interactions

8.29. Alcohol consumption increases dopamine

Alcohol consumption increases dopamine.73

8.30. Carbohydrates increase dopamine

Carbohydrate consumption (fast food) increases dopamine.73

8.31. GABA inhibited dopamine

GABA, which binds to GABA-B receptors, inhibits and regulates the release of dopamine in the VTA. VTA dopamine addresses the nucleus accumbens.73


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