1. Control ranges through dopamine

• 1.1. Behavior regulated by dopamine
• 1.2. Dopamine and melatonin: waking/sleeping behavior, circadian rhythm
• 1.3. Other influences of dopamine
  • 1.3.1. DARPP-32
  • 1.3.1. Nf-kB

1.1. Behavior regulated by dopamine¶

• Drive
• Motivation
  • Dopamine activates the striatum¹²
    Dopamine deficiency in the striatum can cause anhedonia (disinterest)
  • D2 receptors in the reinforcing system (striatum) are involved in dysfunctional reward behavior³
  • Dopamine appears to primarily regulate wanting, rather than liking or learning⁴
• Attention
  • Dopamine addresses the anterior attention center in the frontal brain¹
    ⇒ The dopaminergic and noradrenergic attentional centers
  • Switching attention⁵
• Activity
• Fine motor skills¹
  • Dopamine deficiency causes control problems: imprecise motor activity on the one hand (spidery writing) and overshooting motor activity on the other (hyperactivity)
  • D1 receptors in the PFC are involved in dysfunctional inhibition³
• Behavioral Control¹
  • Situational recall of behaviors, especially in response to emotions⁶
  • Control of the intensity of the stress response⁷⁸
• Affect Control⁷
• Synaptic plasticity^91011121314
  • Among other things, the PFC forms long-term memory for abstract rules or strategies using long-term potentiation (LTP) as a form of synaptic plasticity.
  • Medium tonic dopamine levels facilitate the induction of LTP, too high or too low dopamine levels worsen it (inverted U function)
  • Induction of LTD by low-frequency stimuli occurs independently of tonic dopamine by endogenous, phasically released dopamine during stimuli.
    LTP is inhibited by
    • Blockade of dopamine receptors during stimuli
    • Inhibition of dopamine transporter activity.
• Eye blink rate
  • Dopamine increases the blink rate; dopamine deficiency decreases it.¹⁵¹⁶
  • Eyelid blink rate is discussed as a biomarker of striatal D2 and D3 receptor activity.¹⁷¹⁸
  • A decreased eyelid blink rate has been observed in ADHD,¹⁹²⁰ which increased with stimulants.²⁰ One study found no relevant difference in eyelid blink rate in children with ADHD.²¹ One study, which does not reflect whether the ADHD subjects were medicated, found higher eyelid blink rates in children with ADHD.²² One study found increased eyelid blink rates in children with ADHD who had been unmedicated for 24 hours in boys only.²³
  • In healthy adults, decreased blink rate correlated with impulsivity.²⁴
• Immune system²⁵
  • Overview in Broome et al²⁶
  • B lymphocytes, T lymphocytes, natural killer cells, dendritic cells, and macrophages possess dopamine, norepinephrine, and epinephrine receptors.
    • They can be independent of the system of nerve cells²⁶
      • Produce dopamine
      • Store dopamine
      • Resume dopamine
      • Break down dopamine
      • Lymphocytes also norepinephrine
    • Dopamine is involved in the regulation of inflammation. Depending on the dopamine level and dopamine receptor, dopamine acts²⁷
      • 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 brain²⁶
        • CNS neuroinflammation: inflammatory processes in the neuronal tissues of the brain
        • Regulated by 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
            • Schizophrenia
            • Mood disorders
          • The chronic neuroinflammation that occurs in these disorders promotes infiltration of peripheral immune cells of the adaptive and innate immune systems into the site of inflammation
          • Dopamine acts in glia as well as in peripheral immune cells as a neurotransmitter and as an immune transmitter.
      • Microglia
        • Save unknown
        • Receptors: D1, D2, D3, D4
        • Microglia types:
          • M0 phenotype
            • Dormant
          • M1
            • Classically activated
            • Neurotoxic
            • Pro-inflammatory
          • M2a
            • Alternatively activated
            • 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
        • Degradation unknown
        • Receptors: D1, D2, D3, D4, D5
      • Dendritic cells
        • Receptors: D1, D2, D3, D4, D5
      • Neutrophils
        • Receptors: D1, D2, D3, D4, D5
      • NK cells (natural killer cells)²⁸
        • Receptors:
          • D1 (?) and D5: enhanced cytotoxic activity
          • D5: Inhibition of cell proliferation and IFN-γ production in activated (not in resting) NK cells
          • D2, D3, and D4: attenuated cytotoxic activity (Talhada et al., 2018).
    • Cells of the acquired immune system:
      • Oligodendrocytes
        • Synthesis, storage, reuptake, degradation unknown
        • Receptors: D2, D3
      • Monocytes
        • Degradation 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

Dopamine modulates non-dopaminergic signaling. Disturbances in dopamine balance can impair glutamatergic and GABAergic signal transmission.²⁹

Dopamine can increase and decrease the excitability of mPFC neurons-suggesting differential modulation by dopamine depending on mPFC cell type or projection target.³⁰

In principle, the firing rate of dopaminergic neurons increases with anticipated reward. However, there also seem to be dopaminergic neurons that become more active during stress.³¹

1.2. Dopamine and melatonin: waking/sleeping behavior, circadian rhythm¶

Dopamine, together with melatonin, is involved in the regulation of fatigue and sleep.

The dopaminergic system is influenced by the circadian system.³³³⁴
Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is controlled by dopamine as well as by melatonin. The retina transmits light information to the suprachiasmatic nucleus, which is the master biological clock. The suprachiasmatic nucleus sends timing information for rhythmic regulation of dopaminergic brain regions and the behavior controlled by them (locomotion, motivation). Dopamine produced in the substantia nigra and ventral tegmentum may be rhythmically regulated by the suprachiasmatic nucleus via various neural pathways (including by means of the orexin system or the medial preoptic nucleus of the hypothalamus).³⁵

Impaired dopamine synthesis in the retina leads to impaired circadian rhythm functions.³⁸ Dopamine and melatonin inhibit each other.³⁹ Dopamine 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.⁴⁰⁴¹

The photopigment melanopsin in ipRGCs is most sensitive to blue light.⁴²⁴³ In addition to projecting to the suprachiasmatic nucleus, ipRGCs also project to sleep-promoting neurons in the ventrolateral preoptic nucleus and superior colliculus.⁴⁴ The suprachiasmatic nucleus synchronizes multiple peripheral clocks that together control circadian rhythmicity.⁴⁵

A dopamine deficiency (as is typical for ADHD) could therefore cause too little melatonin inhibition during the day. This could possibly explain the severe daytime sleepiness reported by some ADHD patients. Difficulty falling asleep, on the other hand, is more likely to result from an impairment of the circadian rhythm and a resulting existing melatonin deficiency and more likely to occur despite the lower dopamine level in ADHD than to follow from it.

1.3. Other influences of dopamine¶

Dopamine influences very many areas of the brain. At this point we begin to collect these mechanisms.

1.3.1. 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 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 dopaminoceptive cells.⁴⁶⁴⁷
DARP-32 can be found in

• Amygdala
• Nucleus Caudatus / Putamen
• Nucleus accumbens.

1.3.1. Nf-kB¶

Dopamine inhibits nN-kB.