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2. The 4 dopaminergic systems of the brain

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2. The 4 dopaminergic systems of the brain

2. The 4 dopaminergic systems of the brain

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

  • Mesolimbic system (2.1.)
  • Mesocortical system (2.2.)
  • Mesostriatal (nigrostriatal) system (2.3.)
  • Tuberoinfundibular system (2.4.)

This correlates with the fact that the location of a dopamine level change in the brain encodes different behaviors.

In rats running through a maze, a steady increase in the level of dopamine in the striatum was observed, which had its maximum at the exit of the maze.2 Possibly this encodes the time estimation until the expected reward.

The dopamine level changes shown in 1.1. affect the (left) reinforcement center in the striatum (there the nucleus accumbens) and the ventromedial PFC.3 In contrast, dopamine has other functions in other brain areas. For example, high levels of dopamine in the (bilateral) insula reduce the willingness to exert effort to obtain rewards. The insula is thought to have the function of evaluating the cost of effort.3

Most midbrain dopamine neurons fire tonic clocking firing at 0.2-10 Hz and can switch to phasic synchronous burst firing to control behaviors.4

Dopamine neurons can be identified by detecting their tyrosine hydroxylase immunoreactivity:5

  • 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

2.1. The mesolimbic system

Part of the dopaminergic focusing, reinforcing, and motivational system (another part: the mesocortical system).6

The mesolimbic dopamine system includes dopaminergic neurons in Brodmann area 10 in the ventral tegmentum of the midbrain, where dopamine is produced that is projected to:78

  • 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/unpleasure) and reward processing.
Dopamine deficiency in or injury to the nucleus accumbens causes a decreased ability to delay reward.9
Dopamine controls motor behavioral processes in the mesolimbic system in the context of reward (approach to desired things) and response to novel stimuli.10

Malfunctions of the mesolimbic system:

  • For ADHD:
    • Problems of the reinforcement mechanisms11
    • Reward deferral aversion (devaluation of later rewards)7
    • Delay aversion, impatience11
    • Frustration tolerance reduced7
    • Hyperactivity, especially in new situations1112
    • Impulsivity1112
    • Behavioral inhibition/behavioral suppression disorders11
    • Changeable behavior11
    • Continuous attention disorder11
  • In schizophrenia due to dopamine excess:
    • Auditory hallucinations (positive symptom)13
    • Thinking disorders (positive symptom)14

Activation through15

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

2.2. The mesocortical system

Second part of the dopaminergic focusing, reinforcing, and motivating system (first part: the mesolimbic system).6

It includes connections from Brodmann area 10 in the ventral tegmentum of the midbrain, where dopamine is produced, to the1667

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

where the dopamine release occurs.

Malfunctions of the mesocortical system:

  • For ADHD:
    • Underactivation of the frontal system (dopamine deficiency in the PFC)7
    • Executive function limitations117
      • Poor behavior planning
    • Attention Deficit Disorder7
      • Disturbed orientation reactions11
      • Disturbed gaze tracking movements11
      • Reduced focused attention11
    • Cognitive deficits12
  • In schizophrenia due to dopamine deficiency here:
    • Attention deficits (positive symptom)17
    • Affect flattening (negative symptom)17
      *Alogy (thought disorder with impoverishment of speech, lack of language and prolonged response time)17
      *Apathy = apathy, lack of excitability (not sexual)17
    • Anhedonia18
      Anhedonia (inability to enjoy, decreased sensation of pleasure) is also common in ADHD.

Dopamine deficiency in the mesocortical system leads to dopamine excess in the nigrostriatal system, causing further hyperactivity and impulse problems.19

Activation through6

  • 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), whereas lack of inhibition of emotion regulation is caused noradrenergically by the hippocampus.20 Therefore, the former is likely to be more amenable to dopaminergic treatment, whereas emotion regulation and affect control are likely to be better treated noradrenergically.

2.3. The nigrostriatal system

It involves dopaminergic neurons in the substantia nigra pars compacta that project to the basal ganglia/dorsal striatum,7 and is mainly associated with motor control4 and action selection.21
In ADHD, the dorsal striatum is the major nigrostriatal brain region.

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 problems227
      • Other view: hyperactivity rather symptom of deficits of the mesolimbic system12
    • Impulsivity
      • Due to dopaminergic overactivity in the nigrostriatal system caused by a dopamine deficit in the mesocortical dopamine system, which mediates attention problems22
      • Other view: hyperactivity rather symptom of deficits of the mesolimbic system12
    • Disorders of movement modulation / fine motor skills11
    • Impaired nondeclarative (implicit) learning11
    • Memory problems11
    • Behavioral inhibition problems11
    • Cognitive deficits12
  • In Huntington’s disease:
    • Hyperkinetic movement disorders23
  • Tic Disorders23
  • 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

2.4. The tuberoinfundibular system

It includes connections from the arcuate nucleus to the anterior pituitary.24

2.4.1. Dopamine and prolactin

Dopamine inhibits the release of prolactin.

  • Dopamine deficiency, e.g., due to blocked dopamine receptors in the tuberoinfundibular system, consequently increases prolactin secretion from the pituitary gland, the 2nd stage of the HPA axis.
  • Prolactin has a circadian rhythm
    • Maximum levels during non-REM sleep
    • Great influence on sleep. (70 to 80 % of ADHD sufferers suffer from sleep disorders)
  • Prolactin is a regulator of the emotional stress response. Prolactin is significantly elevated in acute and chronic physical and psychological stress situations25 and in anxiety26.
  • Conversely, high prolactin triggers emotional instability and anxiety perception.
  • Prolactin is also released during orgasm.
  • Prolactin increases the risk of breast cancer.25

Elevated prolactin levels (e.g., due to dopamine deficiency) cause:25

  • Depressive mood / depression
  • Lack of drive
  • General fatigue
  • Exhaustion states
  • Concentration disorders
  • Sleep disorders
  • Mood swings
  • Anxiety
  • Panic attacks
  • Unrest
  • Nervousness
  • Irritability
  • Pain sensitivity
  • Social skills limited
  • Novelty Seeking / Sensation Seeking Reduced
  • Changes of 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 stimulants that regulate dopamine balance are so excellent at treating ADHD symptoms.

Other effects of prolactin:

Influencing homeostasis:27

  • Regulation of the humoral and cellular immune response and in autoimmune diseases (immunomodulation)
  • Increases water transport through the breast cell membrane, sodium reabsorption in the small intestine.
  • Promotion of vascularization

Influence on the central nervous system:27

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

  1. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle, Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 89

  2. Howe, Tierney, Sandberg, Phillips, Graybiel (2013): Prolonged Dopamine Signalling in Striatum Signals Proximity and Value of Distant Rewards; Nature. 2013 Aug 29; 500(7464): 575–579. doi: 10.1038/nature12475; PMCID: PMC3927840; NIHMSID: NIHMS507218

  3. Treadway, Buckholtz, Cowan, Woodward, Li, Ansari, Baldwin, Schwartzman, Kessler, Zald (2012): Dopaminergic Mechanisms of Individual Differences in Human Effort-Based Decision-Making; Journal of Neuroscience 2 May 2012, 32 (18) 6170-6176; DOI: http://dx.doi.org/10.1523/JNEUROSCI.6459-11.2012

  4. Liu, Kaeser (2019): Mechanisms and regulation of dopamine release. Curr Opin Neurobiol. 2019 Aug;57:46-53. doi: 10.1016/j.conb.2019.01.001. PMID: 30769276; PMCID: PMC6629510.

  5. Baik (2020): Stress and the dopaminergic reward system. Exp Mol Med. 2020 Dec;52(12):1879-1890. doi: 10.1038/s12276-020-00532-4. PMID: 33257725; PMCID: PMC8080624. REVIEW

  6. Edel, Vollmoeller (2006): ADHS bei Erwachsenen, Seite 110

  7. Müller, Candrian, Kropotov (2011): ADHS – Neurodiagnostik in der Praxis, Seite 83

  8. Gatzke-Kopp, Beauchaine (2007): Central nervous system substrates of impulsivity: Implications for the development of attention-deficit/hyperactivity disorder and conduct disorder. In: Coch, Dawson, Fischer ( Eds): Human behavior, learning, and the developing brain: Atypical development. New York: Guilford Press; 2007. pp. 239–263; 246

  9. Cardinal, Pennicott, Sugathapala, Robbins, Everitt (2001): Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science; (10.1126/science.1060818).

  10. Rensing, Koch, Rippe, Rippe (2006): Der Mensch im Stress; Psyche, Körper, Moleküle, Kapitel 4: neurobiologische Grundlagen von Stressreaktionen, Seite 90

  11. Sagvolden, Johansen, Aase, Russell (2005): A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci. 2005 Jun;28(3):397-419; discussion 419-68.

  12. Gatzke-Kopp, Beauchaine (2007): Central nervous system substrates of impulsivity: Implications for the development of attention-deficit/hyperactivity disorder and conduct disorder. In: Coch, Dawson, Fischer ( Eds): Human behavior, learning, and the developing brain: Atypical development. New York: Guilford Press; 2007. pp. 239–263; 253

  13. Stahl (2000): Essential Psychopharmacology, Neuroscientific Basis and Practical Applications. Second Edition, Cambridge University Press; zitiert nach Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 66

  14. Stahl (2000): Essential Psychopharmacology, Neuroscientific Basis and Practical Applications. Second Edition, Cambridge University Press, zitiert nach Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 66

  15. Edel, Vollmoeller (2006): ADHS bei Erwachsenen, Seite 110, mwN

  16. Le Moal, Simon (1991): Mesocorticolimbic dopaminergic network: functional and regulatory roles; Physiological Reviews. 1 January 1991 Vol. 71 no. 1, 155-234 DOI:

  17. Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 66

  18. Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 66

  19. Castellanos (1997): Toward a pathophysiology of attention-deficit hyperactivity disorder. Clin. Pediatr. 36, 381-393

  20. Müller, Candrian, Kropotov (2011): ADHS – Neurodiagnostik in der Praxis, Seite 85

  21. Liu, Goel, Kaeser (2021): Spatial and temporal scales of dopamine transmission. Nat Rev Neurosci. 2021 Jun;22(6):345-358. doi: 10.1038/s41583-021-00455-7. PMID: 33837376; PMCID: PMC8220193.

  22. Castellanos 1997, zitiert nach Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 67

  23. Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 67

  24. Präsentation zum Thema: “Allgemeine Psychopharmakologie Klinik und Poliklinik für Psychiatrie und Psychotherapie Zentrum Hamburg Eppendorf

  25. Prolaktin: Wikipedia, Stand 04.07.2016

  26. Athanasoulia (2011): Prolaktinome und Psyche, Max Planck Institut für Psychatrie

  27. Pharmawiki.ch: Prolaktin