1. What Is Regulated by Dopamine

Dopamine (3,4-dihydroxytyramine) is the neurotransmitter most closely associated with ADHD.¹
Dopamine is a monoamine, like norepinephrine and epinephrine, which are derived from dopamine. Dopamine is the most abundant monoamine in the brain, accounting for 80% of the total.

Dopamine (like all monoamines) is primarily a volume transmitter. Volume transmitters act like volume controls, amplifying or inhibiting other areas of the brain without directly influencing (synaptic) information processing.² Dopamine controls the signal strength (which signals are relevant), while norepinephrine specifically increases the signal-to-noise ratio ( which signals are salient = noticeable), and serotonin shifts the global network dynamics (e.g., impulsive vs. stable, exploratory vs. conservative) and worsens the signal-to-noise ratio.² To use a musical analogy, monoamines—as volume transmitters—control the volume of entire sections of the orchestra (all violins, all trumpets), while synaptic transmission influences the notes played by individual instruments.
Monoamines modulate attention, for example, by regulating synaptic reinforcement, which activates or deactivates selected neurons in the attentional network.
In addition to its role in volume transmission, dopamine is also involved, to a lesser extent, in information processing as a synaptic neurotransmitter.

In 1910, it was still believed that dopamine was merely an inactive intermediate in the synthesis of catecholamines such as norepinephrine and epinephrine.³ It was not until 1957 that dopamine’s role as a neurotransmitter was discovered.⁴ Carlsson was awarded the Nobel Prize in 2000 for this discovery.⁵

ADHD symptoms are primarily mediated by disorders in the dopaminergic system.

The neurotransmitter dopamine regulates various behaviors such as drive, motivation, attention, activity, fine motor skills, behavioral control, emotional regulation, as well as synaptic plasticity and the blink rate of the eye.
Dopamine also affects the immune system, particularly B lymphocytes, T lymphocytes, natural killer cells, dendritic cells, macrophages, and glial cells. Depending on dopamine levels and the dopamine receptor, dopamine can have either 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 and acts on the suprachiasmatic nucleus, which serves as the body’s master clock. Dopamine and melatonin inhibit each other. A dopamine deficiency (as is typical in ADHD) can disrupt melatonin regulation and the circadian rhythm.

1.1. Dopamine-Regulated Behavior¶

• Drive
• Activity
• Motivation, Reward⁶
  • Dopamine activates the striatum⁷⁸
    A dopamine deficiency in the striatum can cause anhedonia (lack of interest)
  • D2 receptors in the reinforcement system (striatum) are involved in dysfunctional reward behavior⁹
  • Dopamine appears to primarily regulate “wanting,” rather than “liking” or learning¹⁰
• Perception of Novelty, Rewards, and Aversive Stimuli¹¹
• Attention
  • Dopamine acts on the anterior attention center in the frontal lobe⁷
    ⇒ The dopaminergic and noradrenergic attention centers
  • Shifting Attention¹²
• Executive functions¹³
• Motor Initiation and Coordination¹⁴⁶
  • Fine Motor Skills⁷
    • A dopamine deficiency causes control problems: imprecise motor skills on the one hand (scribbled handwriting) and excessive motor activity on the other (hyperactivity)
  • Direction Representation in Movement¹⁵
    • Striatal dopamine and ACh levels correlated strongly with the direction of movement in freely moving mice.
      • Both rose when moving forward or turning to the contralateral side (0°–120°)
      • Both sank toward the ipsilateral side (180°–300°) when moving backward or turning.
      • This pattern became more apparent when the time series of velocity was shifted to the right, suggesting that the peak in velocity precedes that of the photometric signal
    • When initiating movements in selected directions, the dopamine and ACh responses differed
      • Dopamine: increase between 0° and 120°, decrease between 180° and 300°, peak of the dopamine transients approximately 150 ms after the start of movement
      • Note: Not a steady decline, but rather a decline immediately followed by an increase in movement initiation at 180°–300°.
• Inhibition
  • D1 receptors in the PFC are involved in dysfunctional inhibition⁹
• Behavior Management⁷
  • Adapting behavior to the situation, with a particular focus on emotions¹⁶
  • Regulating the Intensity of the Stress Response¹⁷¹⁸
• Emotional Control¹⁷
• Wake-Sleep Behavior, Circadian Rhythm
• Eyes / Vision
• Immune System

Dopamine can both increase and decrease the excitability of mPFC neurons—suggesting that dopamine modulates them differentially depending on the mPFC cell type or projection target.¹⁹

In general, the firing rate of dopaminergic neurons increases in anticipation of a reward. However, there also appear to be dopaminergic neurons that become more active in response to stress.²⁰

Dopaminergic neurons have other functions beyond the release of the neurotransmitter dopamine. These differences become apparent in the case of Parkinson’s disease. In Parkinson’s disease, there is a loss of dopaminergic neurons, not just a decrease in dopamine levels.
A study compared genetic mouse models with identical severe chronic dopamine loss. One mouse line had a widespread loss of dopamine neurons, while the other had only an inactivation of dopamine synthesis in dopamine neurons that were still intact:²²

DA signals reduced by the same amount	Loss of DA neurons	Only DA signal inactivation
Hyperactivity in a new environment	none	none
Motor skills	impaired	impaired
Cognition	is more severely impaired	is impaired
Learning	Significant Shortcomings	Significant Shortcomings
Cue-Discrimination Learning	more severe deficits	significant deficits
Spatial learning	Significant deficits	Remains unchanged
spatial memory	severe deficits	unchanged
Object memory	: drastic deficits	: unchanged

1.2. Synaptic Plasticity¶

The principle attributed to the Hebb²³ —that simultaneous neural activity between two neurons influences their connection, “Cells that fire together, wire together”—can be aptly supplemented with “as long as they get a burst of dopamine.”¹¹, which highlights the importance of dopamine as a neurotrophic substance.²⁴

1.2.1. 3 Types of Synaptic Plasticity¶

There are three main types of synaptic plasticity:⁶

• homosynaptic plasticity (Hebb’s activity-dependent plasticity)²⁵
  • is primarily used for learning and short-term memory
  • requires presynaptic activation of the synapse for induction
  • by definition, occurs only at the synapse that was directly involved in the activation of a cell during induction
  • The strength of the connection between two neurons increases over a longer period of time if the firing of the presynaptic and postsynaptic neurons is closely correlated in time (associative synaptic strengthening)²⁶
  • Synaptic potentiation 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 the cortical neurons of juvenile rodents is modulated by DA.²⁷ STDP is
    • is a form of Hebb’s activity-dependent plasticity for learning and memory
    • is regulated by the temporal synchronization of the spikes from presynaptic 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 following postsynaptic spikes leads to LTD.²⁸
    • Dopamine plays an important modulatory role²⁹
      • extends the time window for detecting matching spikes in the presynaptic and postsynaptic neurons
      • thereby induces t-LTP
• heterosynaptic plasticity³⁰
  • 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, modulatory interneuron, without requiring activity from either the presynaptic or postsynaptic neurons [36].
    • associative heterosynaptic modulation
      • combines homosynaptic and heterosynaptic mechanisms
    • non-associative heterosynaptic modulation
      • purely heterosynaptic,
• homeostatic plasticity (homeostatic synaptic scaling)³¹
  • significant and widespread changes in activity
  • aims to maintain activity levels within an appropriate homeostatic range³²
    • Increased activity in the circuit causes a decrease in the strength of the excitatory synapses
    • A decrease in the circuit’s activity causes an increase in excitatory synapses
  • is triggered by overall activity, regardless of which synapse contributed to the induction
  • proportionally adjusts the weights of all synapses in all cells
  • may include changes in both homosynaptic (active) and heterosynaptic (inactive) inputs²⁵

1.2.2. Dopamine influences synaptic plasticity¶

1.2.2.1. Dopamine regulates LTP¶

Dopamine regulates synaptic plasticity.^{6 333435363738}
Among other things, the PFC forms long-term memory for abstract rules or strategies through long-term potentiation (LTP), a form of synaptic plasticity.
Moderate tonic dopamine levels facilitate the induction of LTP, while dopamine levels that are too high or too low impair it (inverted U-shaped function)

1.2.2.2. Dopamine modulates LTD via D2 receptors through the endocannabinoid anandamide acting on CB1 receptors in the striatum¶

• The induction of LTD by low-frequency stimuli occurs independently of tonic dopamine, via endogenous, phasically released dopamine during the stimuli.
  The LTD is hindered by
  • Blockade of dopamine receptors during stimulation
  • Inhibition of dopamine transporter activity

Dopamine mediates corticostriatal long-term depression (LTD) through the endocannabinoid anandamide (AEA).
D2 receptor agonists increase anandamide (AEA) concentrations in the striatum 8-fold³⁹ by

• Stimulation of AEA synthesis³⁹⁴⁰
  • Other endocannabinoids, such as 2-arachidonylglycerol, remained unchanged³⁹
• Inhibition of AEA degradation by FAAH⁴⁰⁴¹

AEA binds to CB1 receptors. The effect of D2 activation on CB1 (and the associated Parkinson’s symptoms) is blocked by⁴¹

• Inhibition of endocannabinoid reuptake⁴²
• Blockade of postsynaptic AEA uptake⁴²
• Inhibition of AEA degradation⁴³

Chronic administration of D2 antagonists increases CB1 receptor mRNA expression in the striatum.⁴⁴ This upregulation is likely an adaptation to reduced AEA levels.

The CB1 pathway plays a crucial role in mediating the Parkinson’s symptoms that are the consequences of a reduction in LTD.⁴⁵⁴²

CB1 agonists such as anandamide inhibit movement, induce catalepsy, and attenuate amphetamine-induced hyperactivity and stereotypy.⁴⁶⁴⁷
A disorder of the CB1 receptor gene severely impairs motor control.⁴⁸⁴⁹

1.3. Dopamine and Melatonin: Wake-Sleep Behavior, Circadian Rhythm¶

Dopamine, along with melatonin, plays a role in regulating fatigue and sleep.

The dopaminergic system is influenced by the circadian system.⁵⁰⁵¹
Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is regulated by dopamine as well as by melatonin. The retina transmits light information to the suprachiasmatic nucleus, which serves as the body’s master biological clock. The suprachiasmatic nucleus sends timing information to regulate the rhythmic activity of dopaminergic brain regions and the behaviors controlled by them (locomotion, motivation). The dopamine produced in the substantia nigra and the ventral tegmental area may be rhythmically regulated by the suprachiasmatic nucleus via various neural pathways (including the orexin system and the medial preoptic nucleus of the hypothalamus).⁵²

Impaired dopamine synthesis in the retina leads to impaired circadian rhythm functions.⁵⁵ Dopamine and melatonin inhibit each other.⁵⁶ Dopamine is released during the day and inhibits melatonin secretion; conversely, melatonin (which is inhibited by daylight) is released in the evening and at night and inhibits dopamine release.⁵⁷⁵⁸

The photopigment melanopsin in the ipRGCs is most sensitive to blue light.⁵⁹⁶⁰ In addition to projecting to the suprachiasmatic nucleus, the ipRGCs also project to sleep-promoting neurons in the ventrolateral preoptic nucleus and the superior colliculus.⁶¹ The suprachiasmatic nucleus synchronizes several peripheral clocks, which together control the circadian rhythm.⁶²

A dopamine deficiency (as is typical of ADHD) could therefore result in insufficient inhibition of melatonin during the day. This might help explain the severe daytime sleepiness reported by some people with ADHD. Difficulty falling asleep, on the other hand, is more likely to result from a disruption of the circadian rhythm and a resulting melatonin deficiency—and is more likely to occur despite the lower dopamine levels associated with ADHD rather than as a direct consequence of them.

1.4. 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 protein kinase A in response to dopamine and is found in D1 dopamine receptors. The phosphorylation state of DARPP-32 can be regulated by dopamine and cyclic AMP. DARPP-32 appears to play a role in mediating certain effects of dopamine on dopaminergic cells.⁶³⁶⁴
DARP-32 can be found in

• Amygdala
• Caudate Nucleus / Putamen
• Nucleus accumbens.

1.5. NF-κB¶

Dopamine inhibits NF-κB.

1.6. Dopamine Affects the Eyes and Vision¶

1.6.1. Nearsightedness¶

• A lack of bright daylight (outdoors) increases the risk of nearsightedness (myopia)
• The increase in nearsightedness due to a lack of daylight is mediated by dopamine⁶⁵⁶⁶
• The release of dopamine in the retina slows the progression of nearsightedness⁶⁷
• People with ADHD are 22%⁶⁷ to 29%⁶⁸ more likely to have nearsightedness
• People with ADHD who take ADHD medications have a 39% lower risk of myopia. Taking multiple ADHD medications reduced the risk more than taking a single ADHD medication.⁶⁷
• People with ADHD are 67% more likely to have farsightedness⁶⁸

1.6.2. Eyelid blink rate¶

Dopamine increases the blink rate; a dopamine deficiency decreases it.⁶⁹⁷⁰
Blink rate is discussed as a biomarker for the activity of striatal D2 and D3 receptors.⁷¹⁷²
The body of research on blink rate in ADHD is inconclusive.

• reduced blink rate
  • For ADHD: ⁷³⁷⁴
  • which was exacerbated by stimulants.⁷⁴
  • In healthy adults, a reduced blink rate was correlated with impulsivity.⁷⁵
• unchanged blink rate
  • Blink rate remains unchanged in children with ADHD⁷⁶
• higher blink rates
  • in children with ADHD, although the study did not specify whether the people with ADHD were taking medication⁷⁷
  • only among boys with ADHD. These boys had not taken any medication for 24 hours.⁷⁸

1.7. Dopamine Affects the Immune System¶

Dopamine plays a role in regulating the immune system.⁷⁹ Overview by Broome et al.⁸⁰

• B lymphocytes, T lymphocytes, natural killer cells, dendritic cells, and macrophages have dopamine, norepinephrine, and epinephrine receptors.
  • They can function independently of the nervous system:⁸⁰
    • Produce dopamine
    • Store dopamine
    • Reabsorb dopamine
    • Break down dopamine
    • Lymphocytes and norepinephrine

• Dopamine plays a role in regulating inflammation. Depending on dopamine levels and dopamine receptors, dopamine acts⁸¹
  • 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 brain⁸⁰
    • CNS Neuroinflammation: Inflammatory Processes in the Brain’s Neural Tissues
    • Regulated through 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
      • Including:
        • Parkinson’s
        • Schizophrenia
        • Mood Disorders
      • The chronic neuroinflammation that occurs in these Disorders promotes the infiltration of peripheral immune cells from the adaptive and innate immune systems into the site of inflammation
      • Dopamine acts as both a neurotransmitter and an immunotransmitter in glial cells and peripheral immune cells.
  • Oligodendrocytes
    • Synthesis, storage, uptake, and breakdown are unknown
    • Receptors: D2, D3
  • Microglia
    • Save unknown
    • Receptors: D1, D2, D3, D4
    • Types of microglia:
      • M0 phenotype
        • Inactive
      • M1
        • Classically activated
        • Neurotoxic
        • Pro-inflammatory
      • M2a
        • Alternatively enabled
        • Neuroprotective
        • Anti-inflammatory
      • M2b
        • Type II alternative activation
      • M2c
        • Acquired deactivation
  • Astrocytes
    • Receptors: D1, D2, D3, D4, D5
• Cells of the innate immune system:
  • Macrophages
    • Mining history unknown
    • Receptors: D1, D2, D3, D4, D5
  • Dendritic cells (link the innate and adaptive immune responses)
    • Receptors: D1, D2, D3, D4, D5
  • Neutrophils
    • Receptors: D1, D2, D3, D4, D5
  • NK cells (natural killer cells)⁸²
    • Receptors:
      • D1 (?) and D5: increased cytotoxic activity
      • D5: Inhibition of cell proliferation and IFN-γ production in activated (but not quiescent) NK cells
      • D2, D3, and D4: reduced cytotoxic activity
  • Mast cells
    • Resumption and dismantling unknown
  • Monocytes
    • Mining: Unknown
    • Receptors: D1, D2, D3, D4, D5
• Cells of the adaptive immune system:
  • T lymphocytes
    • Receptors: D1, D2, D3, D4, D5
  • B lymphocytes
    • Resumption: Unknown
    • Receptors: D1, D2, D3, D4, D5
  • Eosinophils
    • Synthesis, storage, and recovery: unknown
    • Receptors: D1, D2, D3, D4, D5

1.8. Dopamine affects oxytocin¶

Dopamine receptors are located on the oxytocin neurons within the PVN, and dopamine stimulates the release of oxytocin.⁸³

1.9. Dopamine affects serotonin¶

Disorders in the function of dopaminergic neurons before or during birth, as well as in adulthood, lead to impairments in the serotonin system.⁸⁴

• Pitx3 deficiency leads to the loss of dopamine neurons in the substantia nigra and, to some extent, in the VTA, and indirectly results in the loss of serotonergic function in the striatum.⁸⁴
• 6-OHDA-induced ablation of midbrain dopamine neurons on the 5th day after birth in mice also indirectly leads to 5-HT denervation of the mPFC⁸⁵

1.10. Dopamine affects glutamate and GABA¶

Dopamine modulates non-dopaminergic signaling. Disorders in dopamine levels can disrupt glutamatergic and GABAergic signaling.⁸⁶

1.11. Glial cells¶

Dopamine (and serotonin) appear to activate microglia and thereby cause cellular damage.²

1.12. Dopamine affects blood flow¶

Dopamine affects the cerebral microvasculature by increasing or decreasing blood flow and altering microcirculation in the brain.²