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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
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
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
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.
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
Acute stress increases dopamine and noradrenaline levels even in the presence of chronic stress
In any case, increased levels of dopamine (+ 54 %) and noradrenaline (+ 50 %) were found in the mPFC during purely acute stress. In the case of existing chronic stress, the addition of acute stress increased dopamine by 42% and noradrenaline by 92%.40 Diazepam reduced the increase in dopamine to + 17 % and in noradrenaline to + 42 % only in the case of purely acute stress. In the case of existing chronic stress, diazepam did not reduce the changes in dopamine and noradrenaline when acute stress was added. Note: In this study, “chronic stress” was defined as exposure to cold for three to four weeks. In our opinion, the reduced dopamine and noradrenaline levels in chronic stress, which we have described many times in this project, are the consequences of a significantly longer exposure to stress.
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
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
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
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
The intrinsically photosensitive retinal ganglion cells (ipRGCs) of the M1 type (which are connected to the amacrine cells54 modulate melatonin and dopamine release in addition to the pupillary reflex.55 Unlike the rod and cone photoreceptor cells in the retina, which are responsible for night and color vision, the ipRGCs are responsible for the non-imaging perception of light intensity. These cells are therefore likely to be involved in excessive sensitivity to light due to high sensitivity.
The ipRGCs project via the retinohypothalamic tract into the suprachiasmatic nucleus.
Impaired dopamine synthesis in the retina leads to impaired circadian rhythm functions.56Dopamine and melatonin inhibit each other.57Dopamine 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.
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
