2. The 6 dopaminergic systems of the brain

The brain contains a number of communication systems by means of which certain areas of the brain exchange information with each other (similar to highways within the entire road network) and which each use certain neurotransmitters.
Five of these communication systems are based on an exchange of information via dopamine (dopaminergic pathways):¹

• Mesolimbic dopamine system (2.2.)
• Mesocortical dopamine system (2.3.)
• Mesostriatal (nigrostriatal) dopamine system (2.4.)
• Tuberoinfundibular dopamine system (2.5.)
• Inzertohypothalamic dopamine system (2.6.)

The cerebellum (small brain) has been recognized quite recently as containing its own dopaminergic system:

• Cerebellar dopamine system (2.7.)

There is also the dopaminergic system of the retina, through which bright daylight controls dopamine synthesis in the retina (2.8.1.), which in turn influences the circadian rhythm, as well as dopaminergic cells in the olfactory bulb (2.8.2.).

Some voices question the functional distinction between the mesocorticolimbic and nigrostriatal pathways,² e.g. due to evidence of control of reward and aversion by the substantia nigra pars compacta, suggesting that this structure plays a role in reward, although it is not part of the mesocorticolimbic system, which is understood to be a reinforcement system.³

Within the different dopamine systems, changes in dopamine levels in individual brain regions encode different behaviors.
For example, in rats running through a maze, there is a steady increase in dopamine levels in the striatum, which peaks at the exit of the maze.⁴ This may encode the time estimation until the expected reward.
A high dopamine level in the (bilateral) insula, on the other hand, reduces the willingness to make an effort in order to receive rewards. The insula is said to have the function of evaluating the costs of an effort.⁵

• 2.1. Dopamine neurons in the brain
• 2.2. The mesolimbic dopamine system
• 2.3. The mesocortical dopamine system
• 2.4. The nigrostriatal dopamine system
• 2.5. The tuberoinfundibular system
  • 2.5.1. Dopamine and prolactin
• 2.6. The inzertohypothalamic dopamine system
• 2.7. Cerebellar dopamine system
• 2.8. Other dopaminergic cells
  • 2.8.1. Retina (A17)
  • 2.8.2. Olfactory bulb (A16)

2.1. Dopamine neurons in the brain¶

Dopamine neurons can be identified by determining their tyrosine hydroxylase immunoreactivity:⁶

• Mice: 21,000 to 30,000 TH-positive neurons
• Rats: 45,000 TH-positive neurons
• Primates: 160,000 to 320,000 TH-immunoreactive neurons
• human midbrain: 400,000 to 600,000 TH-positive neurons (dopamine neurons)⁷
  • just under 600,000 for forty-year-olds
  • around 350,000 for sixty-year-olds

Most dopaminergic neurons are projection neurons whose long and widely branched projections form more than a hundred thousand synapses and can therefore simultaneously influence entire cell groups in many different regions of the brain. They therefore have a very strong influence on neuronal processes and behavior.⁷ Human dopamine neurons of the substantia nigra are said to form over a million synapses and can have a total axon length of more than 4 m⁸ and therefore take several years to grow. Accordingly, brain development disorders often cause disorders in the dopaminergic system.⁷

Dopaminergic nerve cells are found:⁹

• in the ventral midbrain (predominantly), also in the ventral diencephalon
  • 90 % of all dopaminergic cells⁷
  • Substantia nigra, A9
    • Pars reticulata
    • Pars compacta (contains more than 70 % of all dopamine neurons)⁷
  • VTA, A10
  • Nucleus retrorubricus, retrorubral field, A8
• in the telencephalon
  • only a few thousand DA neurons per hemisphere in total⁷
  • in the glomerular layer of the olfactory bulb, A16¹⁰
  • in the amacrine cell population of the retina, A17
• in the diencephalon
  –> Inhibition of prolactin production
  • hypothalamic arcuate nucleus, A12
  • subparafascicular thalamic nucleus, A11
    –> Innervation of the superior olivary complex and the inferior colliculus in the brain stem, A13 (regulation of auditory processing)
  • medial and anterior hypothalamus, A14
• in the midbrain
  • in the rostral half of the periaqueductal gray (substantia grisea periaquaeductalis, central cave gray) of the midbrain, a very small dopaminergic cell group called Aaq is found in primates⁷

A15¹¹

• only exists in a few species (e.g. sheep, rodents, primates)
• is immunoreactive for tyrosine hydroxylase, a precursor of dopamine
• is located
  • in ventral and dorsal components within the preoptic periventricular nucleus
  • in adjacent parts of the anterior hypothalamic region
  • A15 connects caudally to the dopaminergic group A14.

Specification, differentiation and maturation of dopaminergic neurons in the ventral midbrain is a complex process, influenced by various mechanisms, such as:⁹

• Neurulation
• Proliferation
• Differentiation of progenitor cells
• Migration
• Formation of synapses
• Formation of neuronal circuits

These mechanisms involved in the control of dopaminergic functions are controlled by external signals, such as

• Morphogens
• Growth factors
• Activation of specific gene cascades
• Activation of cellular interactions

2.2. The mesolimbic dopamine system¶

Part of the dopaminergic focusing, reinforcement and motivation system (sometimes also called the mesencephalic dopaminergic system or mesolimbocortical system; another part: the mesocortical system).¹²¹³
The mesolimbic, mesocortical and nigrostriatal dopamine systems consist of dopaminergic neurons with very long axons that address distant regions of the brain.¹⁴

The mesolimbic dopamine system comprises dopaminergic neurons in the ventral tegmentum (VTA) of the midbrain, in which dopamine is formed and projected to the:¹⁵¹⁶

• Nucleus accumbens in the ventral striatum
• Hippocampus (part of the limbic system)
• Amygdala (part of the limbic system)
• Septum

The limbic system controls emotional experience, its expression (pleasure / displeasure) and reward processing.
Dopamine deficiency in or injury to the nucleus accumbens results in a reduced ability to delay reward.¹⁷
Dopamine controls motor behavioral processes in the mesolimbic system in the context of reward (approaching desired objects) and reaction to novel stimuli.¹⁸

Malfunctions of the mesolimbic system:

• With ADHD:
  • Problems with reinforcement mechanisms¹⁹
  • Reward deferral aversion (devaluation of later rewards)¹⁵
  • Delay aversion, impatience¹⁹
  • Reduced frustration tolerance¹⁵
  • Hyperactivity, especially in new situations¹⁹²⁰
  • Impulsiveness¹⁹²⁰
  • Disorders of behavioral inhibition/behavioral suppression¹⁹
  • Changeable behavior¹⁹
  • Disorder of sustained attention¹⁹
• In schizophrenia due to excess dopamine:
  • Auditory hallucinations (positive symptom)²¹
  • Thinking disorders (positive symptom)²²

Activation through²³

• Central stimulants
  • Nicotine
  • Apomorphine
  • Amphetamines
  • Cocaine
• Mixed inhibiting-stimulating or euphoric substances
  • Alcohol
  • Cannabis
  • Opioids

2.3. The mesocortical dopamine system¶

Second part of the dopaminergic focusing, reinforcement and motivation system (sometimes also called the mesencephalic dopaminergic system; first part: the mesolimbic system).¹³

The mesolimbic, mesocortical and nigrostriatal dopamine systems consist of dopaminergic neurons with very long axons that address distant regions of the brain.¹⁴
It comprises connections from the VTA in Brodmann area 10 of the midbrain, where dopamine is formed, to the²⁴¹³¹⁵

• PFC
  • The most important mesocortical brain region in ADHD
• Orbitofrontal cortex (OFC)
• Ventral cingulate gyrus

where the dopamine is released.

Dysfunctions of the mesocortical system:

• For ADHD:
  • Underactivation of the frontal system (dopamine deficiency in the PFC)¹⁵
  • Restrictions of executive functions¹⁹¹⁵
    • Poor behavioral planning
  • Attention deficit disorders¹⁵
    • Disturbed orientation reactions¹⁹
    • Disturbed eye movements¹⁹
    • Reduced focused attention¹⁹
  • Cognitive deficits²⁰
• In schizophrenia due to dopamine deficiency here:
  • Attention deficit disorder (positive symptom)²⁵
  • Flattening of affect (negative symptom)²⁵
    *Alogia (thought disorder with speech impoverishment, poor speech and prolonged response time)²⁵
    *Apathy = apathy, lack of excitability (non-sexual)²⁵
  • Anhedonia²⁶
    Anhedonia (inability to enjoy, reduced sense of pleasure) is also common in ADHD.

Dopamine deficiency in the mesocortical system leads to dopamine excess in the nigrostriatal system, which causes further hyperactivity and impulse problems.²⁷

Activation through¹³

• Central stimulants
  • Nicotine
  • Apomorphine
  • Amphetamines
  • Cocaine
• Mixed inhibiting-stimulating or euphoric substances
  • Alcohol
  • Cannabis
  • Opioids

Only the ADHD symptom of lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen), while the lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.²⁸ Therefore, the former may be more amenable to dopaminergic treatment, while emotion regulation and affect control may be more amenable to noradrenergic treatment. This is consistent with our experience that atomoxetine optimizes emotional dysregulation in ADHD better than stimulants.

Compared to mesolimbic or nigrostriatal dopamine neurons, mesocortical DA neurons have

• higher tonic rate of fire²⁹³⁰³¹
  • mesoprefrontal dopamine neurons had mean discharge rates of 9.3 spikes/s and intense burst activity
  • mesocingulate dopamine neurons 5.9 spikes/s and intense burst activity
  • mesopiriform dopamine neurons 4.3 spikes/s and moderate burst activity
  • nigrostriatal dopamine neurons 3.1 spikes/s and moderate burst activity
• more frequent burst firing³²³⁰³¹
• higher dopamine turnover rate (2 to 4-fold)³³³⁰³¹
• a greatly reduced responsiveness to DA agonists and antagonists³⁰³¹
• a lack of tolerance to the effect of chronically administered DA antagonists³⁰³¹
• selective activation through stress³⁴, e.g. foot shocks³⁰
• reduced development of inactivity induced by depolarization on chronic antipsychotic administration³¹
• Dopamine synthesis
  • no dopamine synthesis³⁴
  • Synthesis in midbrain DA neurons without autoreceptors (mesoprefrontal and mesocingular) is more dependent on the availability of the prodrug tyrosine than in neurons with autoreceptors³¹
• D2 autoreceptors
  • no D2 autoreceptors³⁴
  • much fewer or no D2 autoreceptors on DA neurons projecting to PFC and ACC³¹

2.4. The nigrostriatal dopamine system¶

It involves dopaminergic neurons in the substantia nigra pars compacta that project to the basal ganglia / dorsal striatum (caudate nucleus, putamen),¹⁵ and is mainly associated with motor control³⁵ and action selection.³⁶
In ADHD, the dorsal striatum is the most important nigrostriatal brain region.
The mesolimbic, mesocortical and nigrostriatal dopamine systems consist of dopaminergic neurons with very long axons that address distant regions of the brain.¹⁴ Human dopamine neurons of the substantia nigra could form more than one million synapses and have a total axonal length of more than 4 m⁸

With their dense network, the dopaminergic neurons of the substantia nigra pars compacta “flood” the target regions in the dorsal striatum with dopamine.⁷ In the striatum, dopaminergic fibers form synapses every 4 μm en passant. With a half-life of around 75ms, dopamine can diffuse up to 12 μm away from its release site.³⁷

A cascade-like spiral of projections between the VTA/substantia nigra and nucleus accumbens/striatum has been described. Dopamine neurons in the medial VTA send to medium-sized spiny projection neurons in the ventral striatum, which then project back to more lateral parts of the VTA/SNc complex, from where projections are sent to more dorsal parts of the striatum.³⁸

Malfunctions of the nigrostriatal system:

• For ADHD:
  • Hyperactivity
    • Due to dopaminergic overactivity in the nigrostriatal system caused by a dopamine deficit in the mesocortical dopamine system, which mediates attention problems³⁹¹⁵
    • Other view: Hyperactivity is more likely to be a symptom of deficits in the mesolimbic system⁴⁰
  • Impulsiveness
    • Due to dopaminergic overactivity in the nigrostriatal system caused by a dopamine deficit in the mesocortical dopamine system, which mediates attention problems³⁹
    • Other view: Hyperactivity is more likely to be a symptom of deficits in the mesolimbic system⁴⁰
  • Disorders of movement modulation / fine motor skills¹⁹
  • Impaired non-declarative (implicit) learning¹⁹
  • Memory problems¹⁹
  • Problems of behavioral inhibition¹⁹
  • Cognitive deficits²⁰
• For Huntington’s disease:
  • Hyperkinetic movement disorders⁴¹
• Tic disorders⁴¹
• In Parkinson’s disease due to dopamine deficiency or blockade of dopamine receptors by antipsychotics in this area:
  • Tremor
  • Rigor (muscle rigidity, muscle stiffness)
  • Hypokinesia (lack of movement; slowing of movements, restricted facial expressions)
  • Akinesia

2.5. The tuberoinfundibular system¶

The tuberoinfundibular dopamine system comprises connections from the arcuate nucleus and hypothalamus to the anterior pituitary.⁴²
Unlike dopamine uptake in the mPFC, nucleus accumbens and caudate nucleus/putamen, which correlates with the number of dopamine receptors present, dopamine uptake in the neuroendocrine tuberoinfundibular dopamine system is lower and slower and corresponds to that of the amygdala.⁴³
The tuberoinfundibular system and the inzertohypothalamic dopamine system have medium-length axons.⁴⁴

2.5.1. Dopamine and prolactin¶

Dopamine inhibits the release of prolactin.

• Dopamine deficiency, e.g. due to blocked dopamine receptors in the tuberoinfundibular system, consequently increases the release of prolactin from the pituitary gland, the 2nd increment of the HPA axis.
• Prolactin has a circadian rhythm
  • Maximum levels during non-REM sleep
  • Major influence on sleep. (70 to 80 % of people with ADHD suffer from sleep disorders)
• Prolactin is a regulator of the emotional stress response. Prolactin is significantly increased in acute and chronic physical and psychological stress situations⁴⁵ and in anxiety⁴⁶.
• Conversely, a high prolactin level triggers emotional instability and anxiety.
• Prolactin is also released during orgasm.
• Prolactin increases the risk of breast cancer.⁴⁵

Elevated prolactin levels (e.g. due to a lack of dopamine) cause:⁴⁵

• Depressive mood / depression
• Lack of drive
• General tiredness
• States of exhaustion
• Concentration disorders
• Sleep disorders
• Mood swings
• States of anxiety
• Panic attacks
• Restlessness
• Nervousness
• Irritability
• Sensitivity to pain
• Limited social skills
• Novelty Seeking / Sensation Seeking reduced
• Changes in character

Together with the symptoms of dopamine deficiency in the mesocortical system (anhedonia = mild depression, lack of drive) and the resulting dopamine excess in the nigrostriatal system (hyperactivity, impulse control disorders), this list covers almost all of the typical ADHD symptoms.
This helps explain why dopamine-regulating stimulants are so effective in treating ADHD symptoms.

Other effects of prolactin:

Influencing homeostasis:⁴⁷

• Regulation of the humoral and cellular immune response and autoimmune diseases (immunomodulation)
• Increases water transport through the breast cell membrane, sodium absorption in the small intestine.
• Promotes the formation of new blood vessels

Influence on the central nervous system:⁴⁷

• Activation of dopaminergic cells
  • Thereby self-regulation circle
• Stimulation of the appetite
• Anxiolytic (anxiety-relieving)
• Stress-reducing
• Regulation of oxytocin-producing nerve cells
• Stimulation of myelination in the brain

2.6. The inzertohypothalamic dopamine system¶

In the inzertohypothalamic dopamine system, the dopaminergic neurons are located in the hypothalamus in the catecholaminergic areas A13 and A14. These send their dopaminergic signals to the hypothalamic nuclei (PVN) and the medial preoptic area. The inzertohypothalamic dopamine system controls various functions such as nutrition, erectile function and sexual behavior.⁴⁸
The tuberoinfundibular system and the inzertohypothalamic dopamine system have medium-length axons.⁴⁴

2.7. Cerebellar dopamine system¶

Dopaminergic midbrain nuclei transmit to the cerebellum:{Flace P, Livrea P, Basile GA, Galletta D, Bizzoca A, Gennarini G, Bertino S, Branca JJV, Gulisano M, Bianconi S, Bramanti A, Anastasi G (2021): The cerebellar dopaminergic system. Front Syst Neurosci. 2021 Aug 5;15:650614. doi: 10.3389/fnsys.2021.650614. PMID: 34421548; PMCID: PMC8375553. REVIEW}}

• from VTA (A10)
• from the retrorubral nucleus (A8), weaker
• from the substantia nigra pars compacta (SNpc) (A9), weaker

The cerebellum sends back to these dopaminergic:{Flace P, Livrea P, Basile GA, Galletta D, Bizzoca A, Gennarini G, Bertino S, Branca JJV, Gulisano M, Bianconi S, Bramanti A, Anastasi G (2021): The cerebellar dopaminergic system. Front Syst Neurosci. 2021 Aug 5;15:650614. doi: 10.3389/fnsys.2021.650614. PMID: 34421548; PMCID: PMC8375553. REVIEW}}

• from the vermian cerebellar cortex and from the fastigial nucleus to the ipsilateral VTA
• from the nucleus interpositus and the nucleus dentatus to the contralateral dorsal VTA and the medial and dorsal substantia nigra pars compacta
• 20 % of these fibers were bilateral

The cerebellum (here nucleus dentatus, nucleus fastigialis and nucleus interpositus posterior) is dopaminergically interconnected with VTA, SNpc and nucleus caudatus{Flace P, Livrea P, Basile GA, Galletta D, Bizzoca A, Gennarini G, Bertino S, Branca JJV, Gulisano M, Bianconi S, Bramanti A, Anastasi G (2021): The cerebellar dopaminergic system. Front Syst Neurosci. 2021 Aug 5;15:650614. doi: 10.3389/fnsys.2021.650614. PMID: 34421548; PMCID: PMC8375553. REVIEW}}, just as the neocerebellum is dopaminergically connected to the PFC.⁴⁹

In addition to the dense connections between the cerebellum and PFC, the basal ganglia and the VTA⁵⁰, an independent dopaminergic network exists in the cerebellum ^{51 52 53 5455}
Subgroups of the cerebellum show a structural specialization for cognitive functions.⁵⁶
In the cerebellum, in addition to a number of other dopaminergic mechanisms, there are

• high DAT levels, especially in the posterior-inferior vermis.⁵¹⁵³
• all dopamine receptors (DRD1 to DRD5)⁵¹

Oxygen deprivation in the cerebellum of newborn rats causes a reduction in dopamine levels and reduced expression of DRD1 and DRD2. Administration of glucose, oxygen and adrenaline partially corrects these deficiencies.⁵⁷
A selective reduction of dopaminergic Purkinje neurons of the cerebellum correlated with specific impairments of cognitive functions such as behavioral flexibility, response inhibition and social recognition memory.⁵⁸

Several studies have shown that the cerebellum is involved in dopaminergic neurological and psychiatric disorders such as⁵¹

• ADHD^{59606162636465}
  • MPH also affects cerebellar function in ADHD, suggesting that behavioral changes and even motor changes in children with ADHD taking MPH could be explained by outcomes involving the cerebellum.⁵⁴
• Autism^{665067686369707171727374}
• Parkinson’s disease⁷⁵⁷⁶
  • however, the cerebellum may only be involved here⁷⁷⁷⁸ or also⁷⁹ through compensatory mechanisms
• Schizophrenia⁸⁰⁷⁴
• Drug addiction^8182838485
• spinocerebellar ataxia⁶¹

2.8. Other dopaminergic cells¶

2.8.1. Retina (A17)¶

Dopaminergic cells in the amacrine cell population of the retina, A17, form very short, local axons and connect only the inner and outer plexiform layers of the retina.⁸⁶

A high release of dopamine in the retina adjusts vision to daylight (photopic, cone vision), while a low release adjusts vision to night light (scotopic, rod vision).⁸⁷ Dopamine reduces horizontal cell coupling via the D1 receptor by phosphorylating connexins through protein kinase A, thereby closing the pore.⁷
This may explain the increased sensitivity to light in people with ADHD, as ADHD is associated with reduced dopamine levels,

Bright daylight controls dopamine synthesis in the retina and thus influences the circadian rhythm.

2.8.2. Olfactory bulb (A16)¶

The periglomerular dopamine cells of the olfactory bulb connect mitral cell dendrites in nearby neighboring glomeruli. Here, too, the axons are very short.⁸⁶