2. The 5 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.
Five 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.)
• Inzertohypthalamic system (2.5.)

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
• 2.2. The mesocortical system
• 2.3. The nigrostriatal system
• 2.4. The tuberoinfundibular system
  • 2.4.1. Dopamine and prolactin
• 2.5. The inzertohypthalamic system

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
  • In ADHD the most important mesocortical brain region
• 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
    *Alogia (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
  • Problems of behavioral inhibition¹¹
  • 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 stressful situations²⁵ and 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 levels 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

2.5. The inzertohypthalamic system¶

In the inzertohypthalamic dopamine system, the dopaminergic neurons in the hypothalamus are found in the catecholaminergic areas A13 and A14. These send their dopaminergic signals to the hypothalamic nuclei (PVN) and the medial preoptic area. The inzertohypthalamic dopamine system controls various functions such as feeding, erectile function, and sexual behavior.²⁸