1. What is regulated by dopamine

The neurotransmitter dopamine regulates various behaviors such as drive, motivation, attention, activity, fine motor skills, behavior control, affect control as well as synaptic plasticity and the blink rate of the eye.
Dopamine also acts on the immune system, in particular on B lymphocytes, T lymphocytes, natural killer cells, dendritic cells, macrophages and glial cells. Depending on the dopamine level and dopamine receptor, dopamine can have pro-inflammatory or anti-inflammatory effects.
Dopamine is involved in the regulation of wakefulness and sleep and influences the circadian rhythm. Dopamine is produced rhythmically in the amacrine cells of the retina of the eye and acts on the suprachiasmatic nucleus, which is the master biological clock. Dopamine and melatonin inhibit each other. A dopamine deficiency (as is typical in ADHD) can impair melatonin regulation and the circadian rhythm.

Dopaminergic nerve cells have other functions that go beyond the release of the neurotransmitter dopamine. These differences can be seen in the example of Parkinson’s disease. In Parkinson’s, there is a loss of dopaminergic neurons and not just a reduced dopamine level.
One study compared genetic mouse models with identical severe chronic dopamine loss. One mouse line had a comprehensive loss of dopamine neurons, the other only an inactivation of dopamine synthesis with dopamine neurons still preserved:¹

DA signals reduced to the same extent	DA neuron loss	DA signal inactivation only
Hyperactivity in a new environment	none	none
Motor skills	impaired	impaired
Cognition	more impaired	impaired
Learning	clear deficits	clear deficits
Cue discrimination learning	more serious deficits	significant deficits
spatial learning	drastic deficits	unchanged
spatial memory	drastic deficits	unchanged
Object memory	drastic deficits	unchanged

• 1.1. Behavior regulated by dopamine
• 1.2. Synaptic plasticity
• 1.3. Dopamine and melatonin: waking/sleeping behavior, circadian rhythm
• 1.4. Other influences of dopamine
  • 1.4.1. DARPP-32
  • 1.4.2. NF-kB

1.1. Behavior regulated by dopamine¶

• Drive
• Activity
• Motivation, reward²
  • Dopamine activates the striatum³⁴
    Dopamine deficiency in the striatum can cause anhedonia (lack of interest)
  • D2 receptors in the reinforcement system (striatum) are involved in dysfunctional reward behavior⁵
  • Dopamine appears to primarily regulate wanting, rather than liking or learning⁶
• Perception of novelty, reward and aversive stimuli⁷
• Attention
  • Dopamine addresses the anterior attention center in the forebrain³
    ⇒ The dopaminergic and the noradrenergic attention center
  • Switching the attention⁸
• Executive functions⁹
• Motor initiation and coordination¹⁰²
  • Fine motor skills³
    • Dopamine deficiency causes control problems: inaccurate motor skills on the one hand (spidery handwriting) and excessive motor skills on the other (hyperactivity)
• Inhibition
  • D1 receptors in the PFC are involved in dysfunctional inhibition⁵
• Behavior control³
  • Situationally appropriate recall of behaviors, especially in response to emotions¹¹
  • Controlling the intensity of the stress response¹²¹³
• Affect control¹²
• Synaptic plasticity^{2 141516171819}
  • Among other things, the PFC forms the long-term memory for abstract rules or strategies by means of long-term potentiation (LTP) as a form of synaptic plasticity.
  • Moderate tonic dopamine levels facilitate the induction of LTP, dopamine levels that are too high or too low worsen it (inverted U function)
  • The induction of LTD by low-frequency stimuli occurs independently of tonic dopamine by endogenous, phasically released dopamine during the stimuli.
    The LTP is inhibited by
    • Blockade of the dopamine receptors during the stimuli
    • Inhibition of dopamine transporter activity.
• Immune system²⁰
  • Overview by Broome et al²¹
  • B lymphocytes, T lymphocytes, natural killer cells, dendritic cells and macrophages have dopamine, noradrenaline and adrenaline receptors.
    • They can be independent of the nerve cell system²¹
      • Produce dopamine
      • Store dopamine
      • Resume dopamine
      • Reduce dopamine
      • Lymphocytes also norepinephrine
    • Dopamine is involved in the regulation of inflammation. Depending on the dopamine level and dopamine receptor, dopamine acts²²
      • pro-inflammatory
        • at high-affinity dopamine receptors
          • D3
          • D5
      • anti-inflammatory.
        • at low-affinity dopamine receptors
          • D1
          • D2
    • Glial cells
      • Regulate, among other things, central neuroinflammation in the brain²¹
        • CNS neuroinflammation: inflammatory processes in the neuronal tissues of the brain
        • Regulated by the production of cytokines, chemokines, reactive oxygen species and secondary messengers by microglia and astrocytes
        • Is associated with most CNS pathologies characterized by abnormal dopaminergic signaling
          • Among others:
            • Parkinson’s disease
            • Schizophrenia
            • Mood disorders
          • The chronic neuroinflammation that occurs in these disorders promotes the infiltration of peripheral immune cells of the adaptive and innate immune system into the focus of inflammation
          • Dopamine acts as a neurotransmitter and immunotransmitter in both glial and peripheral immune cells.
      • Microglia
        • Save unknown
        • Receptors: D1, D2, D3, D4
        • Microglia types:
          • M0 phenotype
            • Dormant
          • M1
            • Classically activated
            • Neurotoxic
            • Pro-inflammatory
          • M2a
            • Alternatively activated
            • Neuroprotective
            • Anti-inflammatory
          • M2b
            • Alternative type II activation
          • M2c
            • Acquired deactivation
      • Astrocytes
        • Receptors: D1, D2, D3, D4, D5
    • Cells of the innate immune system:
      • Macrophages
        • Dismantling unknown
        • Receptors: D1, D2, D3, D4, D5
      • Dendritic cells
        • Receptors: D1, D2, D3, D4, D5
      • Neutrophils
        • Receptors: D1, D2, D3, D4, D5
      • NK cells (natural killer cells)²³
        • Receptors:
          • D1 (?) and D5: increased cytotoxic activity
          • D5: Inhibition of cell proliferation and IFN-γ production in activated (not resting) NK cells
          • D2, D3 and D4: attenuated cytotoxic activity
    • Cells of the acquired immune system:
      • Oligodendrocytes
        • Synthesis, storage, reuptake, degradation unknown
        • Receptors: D2, D3
      • Monocytes
        • Dismantling unknown
        • Receptors: D1, D2, D3, D4, D5
      • T lymphocytes
        • Receptors: D1, D2, D3, D4, D5
      • B lymphocytes
        • Resumption unknown
        • Receptors: D1, D2, D3, D4, D5
      • Eosinophils
        • Synthesis, storage, recovery unknown
        • Receptors: D1, D2, D3, D4, D5
      • Mast cells
        • Resumption and dismantling unknown
• Waking/sleeping behavior, circadian rhythm
• Eyes
  • A lack of bright daylight (outside) increases the risk of short-sightedness (myopia)
  • The increase in myopia due to lack of daylight is mediated by dopamine²⁴²⁵
  • People with ADHD are 29% more likely to suffer from short-sightedness and 67% more likely to suffer from long-sightedness²⁶
  • Blink rate of the eye
    • Dopamine increases the blink rate, dopamine deficiency reduces it.²⁷²⁸
    • The blink rate is discussed as a biomarker for the activity of striatal D2 and D3 receptors.²⁹³⁰
    • A reduced blink rate was observed in ADHD,³¹³² which increased with stimulants.³² One study found no relevant difference in blink rate in children with ADHD.³³ One study, which does not reflect whether the persons with ADHD were medicated, found higher blink rates in children with ADHD.³⁴ One study found increased blink rates in children with ADHD who had been unmedicated for 24 hours only in boys.³⁵
    • In healthy adults, a reduced blink rate correlated with impulsivity.³⁶
      Dopamine modulates non-dopaminergic signal transmission. Disorders in the dopamine balance can impair glutamatergic and GABAergic signal transmission.³⁷

Dopamine can increase and decrease the excitability of mPFC neurons - suggesting differential modulation by dopamine depending on mPFC cell type or projection target.³⁸

In principle, the firing rate of dopaminergic neurons increases when a reward is expected. However, there also appear to be dopaminergic nerve cells that become more active under stress.³⁹

1.2. Synaptic plasticity¶

The theorem attributed to Hebb⁴¹ that the simultaneous neuronal activity of two neurons influences their connection, “Cells that fire together, wire together”, can easily be supplemented by “as long as they get a burst of dopamine.”⁷, which emphasizes the importance of dopamine as a neurotrophic substance⁴²

There are 3 main types of synaptic plasticity²

• homosynaptic plasticity (Hebbian activity-dependent plasticity)⁴³
  • is primarily used for learning and short-term memory
  • requires presynaptic activation of the synapse for induction
  • by definition only occurs at the synapse that was directly involved in the activation of a cell during induction
  • the strength of the connection between two neurons is increased over a longer period of time if the firing of the pre- and postsynaptic neurons is closely correlated in time (associative synaptic strengthening)⁴⁴
  • the synaptic amplification is input-specific
    • if two neurons fire together, their synapse is strengthened, other synapses on both neurons remain unchanged
  • homosynaptic plasticity is involved in
    • Refinement of connectivity during development (“neurons that fire together, wire together”)
    • Extraction of causal relationships between events in the environment in classical conditioning (Pavlovian conditioning)
    • associative learning
    • motor learning
  • Spike timing-dependent plasticity (STDP) in juvenile rodent cortical neurons is modulated by DA.⁴⁵ STDP is
    • is a form of Hebbian activity-dependent plasticity for learning and memory
    • is regulated by the temporal coupling of the spikes of pre- and postsynaptic neurons
    • the repeated arrival of presynaptic spikes a few milliseconds before postsynaptic action potentials leads to LTP at the synapse
    • the repeated arrival of presynaptic spikes after postsynaptic spikes leads to LTD.⁴⁶
    • Dopamine has an important modulating role⁴⁷
      • extends the time window for the detection of matching spikes in the pre- and postsynaptic neurons
      • thereby induces the t-LTP
• heterosynaptic plasticity⁴⁸
  • is not limited to active synapses
  • can also be induced at synapses that were not active during the induction of homosynaptic plasticity
  • heterosynaptic plasticity is involved in
    • Strengthening synaptic connections
      • a synapse can be strengthened or weakened by the firing of a third, modulating interneuron without requiring the activity of any of the pre- or postsynaptic neurons [36].
    • associative heterosynaptic modulation
      • combines homosynaptic and heterosynaptic mechanisms
    • non-associative heterosynaptic modulation
      • purely heterosynaptic,
• homeostatic plasticity (homeostatic synaptic scaling)⁴⁹
  • strong and extensive changes in activity
  • aims to maintain the activity level in an appropriate homeostatic range⁵⁰
    • increased activity of the circuit causes a decrease in the strength of the excitatory synapses
    • Decrease in circuit activity causes increase in excitatory synapses
  • is triggered by overall activity, regardless of which synapse contributed to the induction
  • changes the weights of all synapses of all cells proportionally
  • may include changes in homosynaptic (active) and heterosynaptic (inactive) inputs⁴³

1.3. Dopamine and melatonin: waking/sleeping behavior, circadian rhythm¶

Together with melatonin, dopamine is involved in the regulation of tiredness and sleep.

The dopaminergic system is influenced by the circadian system.⁵¹⁵²
Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is controlled by dopamine as well as melatonin. The retina transmits light information to the suprachiasmatic nucleus, which is the master biological clock. The suprachiasmatic nucleus sends timing information for the rhythmic regulation of dopaminergic brain regions and the behavior controlled by them (locomotion, motivation). The dopamine produced in the substantia nigra and the ventral tegmentum is possibly rhythmically regulated by the suprachiasmatic nucleus via various nerve pathways (including the orexin system or the medial preoptic nucleus of the hypothalamus).⁵³

Impaired dopamine synthesis in the retina leads to impaired circadian rhythm functions.⁵⁶ Dopamine and melatonin inhibit each other.⁵⁷ Dopamine is released during the day and inhibits melatonin secretion, and conversely melatonin (which is inhibited by daylight) is released in the evening and at night and inhibits dopamine release.⁵⁸⁵⁹

The photopigment melanopsin in the ipRGCs is most sensitive to blue light.⁶⁰⁶¹ In addition to projecting to the suprachiasmatic nucleus, the ipRGCs also project to sleep-promoting neurons in the ventrolateral preoptic nucleus and superior colliculus.⁶² The suprachiasmatic nucleus synchronizes several peripheral clocks, which together control the circadian rhythm.⁶³

A dopamine deficiency (as is typical of ADHD) could therefore result in too little melatonin inhibition during the day. This could possibly explain the severe daytime sleepiness reported by some people with ADHD. Difficulty falling asleep, on the other hand, is more likely to be caused by an impairment of the circadian rhythm and a resulting melatonin deficiency and more likely to occur despite the lower dopamine level in ADHD than as a result of it.

1.4. Other influences of dopamine¶

Dopamine influences many areas of the brain. At this point, we begin to collect these mechanisms.

1.4.1. DARPP-32¶

Dopamine/adenosine-3’,5’-monophosphate-regulated phosphoprotein 32 (DARPP-32) is a potent inhibitor of calcium-independent serine/threonine phosphatases.
It is a phosphoprotein that is phosphorylated by dopamine through protein kinase A and is found in D1 dopamine receptors. The phosphorylation state of DARPP-32 can be regulated by dopamine and by cyclic AMP. DARPP-32 appears to be relevant in mediating certain effects of dopamine on dopaminoreceptive cells.⁶⁴⁶⁵
DARP-32 can be found in

• Amygdala
• Caudate nucleus / putamen
• Nucleus accumbens.

1.4.2. NF-kB¶

Dopamine inhibits NF-kB.