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3. Interactions of the dopaminergic brain areas

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3. Interactions of the dopaminergic brain areas

The nucleus accumbens (part of the striatum) plays a central role in the conversion of emotional information into motor actions. It is modulated by the prefrontal cortex (PFC), which in turn receives information from sensory and limbic areas of the brain. The PFC influences dopaminergic and cholinergic neurons in various brain regions that regulate the activity of the nucleus accumbens and other limbic brain areas. The activity of the nucleus accumbens is also influenced by the amygdala and the hippocampus, which send emotional and contextual information to the nucleus accumbens, respectively. There is an interaction between the PFC and subcortical regions (including the striatum) in which a high dopamine level in the PFC correlates with a low dopamine level in subcortical regions and vice versa.
A loss of dopaminergic activity in the PFC leads to increased activity in the nucleus accumbens and can lead to behavioral deficits.
There is also an interaction between the hippocampus, the PFC and the nucleus accumbens, in which the respective activity ratio regulates the activity of the nucleus accumbens. Finally, dopamine plays a role in the functional connectivity between different brain regions.

3. Interactions of the dopaminergic brain areas

3.1. Nucleus accumbens as the control center between emotion and action

The nucleus accumbens (part of the striatum) is the central control center for the “translation” of limbic information into motor responses.

The PFC receives information from the sensory and limbic areas of the brain and in turn projects it to the nucleus accumbens, thereby promoting goal-oriented action.
The medial part of the PFC (mPFC) modulates dopaminergic and cholinergic neurons in the brainstem, basal forebrain and septum, which send information to the nucleus accumbens as well as the amygdala and hippocampus in the limbic system, thereby influencing their activity. The amygdala sends emotional information glutamatergically to the nucleus accumbens, the hippocampus sends contextual information glutamatergically to the nucleus accumbens.

The PFC thus controls cognitive and executive processes that are based on motivation, emotion, learning or memory.123

3.2. The dopamine seesaw between PFC and subcortical regions (e.g. striatum)

High dopamine levels in the PFC cause reduced dopamine levels in subcortical regions and vice versa.

The PFC is glutamatergically activated by the amygdala and hippocampus in relation to the assessment of a situation for its danger potential. Glutamatergic efferents from the mPFC influence the tonic release of dopamine in the nucleus accumbens via presynaptic contacts on dopaminergic nerve endings.
The basolateral amygdala is informed dopaminergically by the PFC about its stress reactions, whereby the amygdala is also addressed dopaminergically by the VTA in a stress-dependent manner.4
The mPFC projects directly and indirectly via the pedunculopotine tegmental nucleus into the ventral tegmentum (VTA), which is the main source of dopamine in the nucleus accumbens.15

Loss of excitatory influence on dopaminergic neurons of the VTA appears to reduce tonic dopamine release in the nucleus accumbens, which in turn leads to sensitization of subcortical dopamine receptors (upregulation). Lesions of the medial PFC - regardless of age - increase subcortical dopaminergic activity, especially in the nucleus accumbens in the striatum, which causes biochemical changes as well as behavioral deficits.6789
It probably depends on which side of the brain the lesion occurs. The dopaminergic activity of subcortical regions apparently depends on the dopamine level in the mPFC in both cerebral hemispheres. Uncontrollable stress increased dopamine especially in the right cortex. Dopamine deficiency in the left or right PFC, mPFC or ACC increased susceptibility to stress. One study found increased stress-induced gastric ulcer formation due to chronic cold stress in rats.10

  • Dopamine deficiency

    • In the right cortex caused10
      • Dopamine levels in the striatum reduced on both sides (in rats)
    • In the left cortex caused10
      • Dopamine turnover in the amygdala increased on both sides (in rats)
    • On both sides of the cortex (in rats)10
      • Dopamine levels in the right nucleus accumbens reduced
      • Increased dopamine turnover in the left nucleus accumbens
      • Dopamine turnover in the right amygdala reduced
      • Increased dopamine levels in the left amygdala
    • In the mPFC caused
      • Increased release of dopamine in the nucleus accumbens11
    • In the PFC caused
      • Even mild stress increases dopamine release in the nucleus accumbens; this increases cortisol levels12(bei neugeborenen Ratten)
    • In the PFC caused
      • Increased amphetamine sensitivity due to increased dopamine sensitivity, which probably results from an increased density of dopamine D2 receptors in the nucleus accumbens.13(bei Ratten)
  • Dopamine release

    • In the PFC causes
      • Reduced dopamine levels in subcortical regions.14
      • Reduced dopamine levels in the striatum14(Rhesusaffen, DA-Stimulation durch Amphetamin)

Oxygen-deprived rats born by caesarean section showed an increased dopaminergic response in the nucleus accumbens, hyperactivity and increased dopamine transporter density in the right PFC. D1 and D2 receptors were unchanged. Under chronic stress, there was also a dopamine deficiency in the right PFC.15

Carriers of the COMT Val/Val polymorphism, which synthesizes more COMT in the PFC, leading to faster dopamine degradation, i.e. lower dopamine levels in the PFC, showed lower tonic and increased phasic dopamine levels in subcortical brain regions.16

There appears to be a kind of “dopamine seesaw” between the PFC and the striatum - at least in healthy people. Low dopamine in the PFC is said to correlate with high dopamine in the striatum and vice versa.
That a mesocortical dopamine deficit leads to a subcortical (mesolimbic) dopamine excess,1718 is consistent with much evidence that mesocortical dopamine exerts a tonic inhibitory influence on subcortical dopamine,1920 21 22 23 24 25 also in the caudate nucleus (in rhesus monkeys and rats).26

However, it is also possible that these are merely temporal differences in an increase, as a study conducted 15 years later found that an amphetamine-induced increase in dopamine in the PFC lasted significantly longer than the increase in the caudate nucleus.27 It is also conceivable that the results found by PET do not match those induced by environmental influences.28

MPFC stimulation appears to induce phasic dopamine release in the nucleus accumbens, with frequency and duration of mPFC stimulation modulating dopamine release in the NAc. Increasing the frequency of direct stimulation of the MFB from 10 - 60 Hz caused an increase in dopamine release.
Increasing the frequency of MFB stimulation increased extracellular dopamine in the NAc, as the rate of stimulated release outpaced uptake kinetics.2930 In another study, dopamine release in the NAc reached its maximum31

  • with an mPFC stimulation duration of 5 s and more at 10 to 20 Hz
  • with an mPFC stimulation duration of less than 5 s at high frequencies such as 60 Hz

3.3. The dopaminergic interaction of the nucleus accumbens, hippocampus and mPFC

A more detailed description of the following presentation can be found in Klein.32

The nucleus accumbens is addressed by the mPFC and the hippocampus. Whether a long-term strengthening of the responses of the nucleus accumbens to stimuli from the PFC or the hippocampus takes place (neurological correlate: long-term potentiation, learning effects) depends on other dopamine levels.
Stimuli from the hippocampus enhanced learning processes in the nucleus accumbens when D1 agonists (stimulating) were given, while D1 antagonists (inhibiting) blocked long-term potentiation.3334
Stimuli from the mPFC enhanced learning processes in the nucleus accumbens when D2 antagonists (inhibitory) were administered, while D1 agonists (stimulatory) blocked long-term potentiation.3334
This leads to the following hypothesis by Goto and Grace:

3.3.1. Activity ratio of hippocampus to mPFC regulates activity of the nucleus accumbens

3.3.1.1. Hippocampus more active than mPFC: nucleus accumbens active

If the hippocampus is more active than the mPFC, the hippocampus transmits to the mPFC.
The consequences are:

  • Nucleus accumbens has increased activity
    • Because the hippocampus and mPFC are active at the same time
    • Total increase in dopamine in the nucleus accumbens
    • Activation of dopaminergic D1 receptors in the nucleus accumbens
      • Due to inhibition of inhibitory connections from the ventral pallidum to the VTA
      • With simultaneous phasic dopamine release,
        • E.g. by excitatory signals from the pedunculopontine tegmental nucleus, which is also innervated by the mPFC
        • D1 receptor stimulation increases calcium influx during NMDA receptor activity
        • Thereby long-term potentiation of the hippocampal inputs.
      • Simultaneous D2 receptor-dependent long-term depression of the prefrontal inputs
        • Probably through various 2nd messenger systems34
          • E.g. the NMDA receptor-induced synthesis of NO
3.3.2.2. MPFC more active than hippocampus: nucleus accumbens inhibited

If the mPFC is more active than the hippocampus, the mPFC transmits to the hippocampus.
The consequences are:

  • Activity of the nucleus accumbens is inhibited
    • Inhibitory projections of the nucleus accumbens
    • Disinhibition of the ventral pallidum
      • Thereby inhibitory projections of the ventral pallidum to the VTA
      • Resulting in reduced tonic dopamine release in the nucleus accumbens
    • Presynaptic D2 receptor activity is reduced
    • Signals from the mPFC to the nucleus accumbens are amplified
    • This results in long-term potentiation of the mPFC inputs34

The long-term potentiation of the inputs to the nucleus accumbens from the hippocampus as well as from the PFC can be reversed by electrical stimulation of nerve fibers with a high repetition frequency (which causes activation) of the respective other region.34

3.4. Interaction locus coeruleus and midbrain

In anesthetized rats, stimulation of the locus coeruleus with a single pulse led to excitation, which was followed by inhibition of the electrical activity of individual dopamine neurons in the midbrain (VTA, substantia nigra). Burst stimulation caused a longer-lasting inhibition. Reserpine suppressed this response, indicating a noradrenergically mediated response.35

3.5. Dopamine and functional connectivity

Dopamine appears to specifically influence the functional connectivity of certain brain regions. According to one study, amisulpride (a D2/D3 antagonist) increased functional connectivity from the putamen to the precuneus and from the ventral striatum to the precentral gyrus. L-DOPA (a dopamine precursor) increased functional connectivity from the ventral tegmentum to the insula and operculum and between the ventral striatum and vlPFC and decreased functional connectivity between the ventral striatum and dorsal caudate with the mPFC.36

3.6. Dopamine elements in different areas of the brain

PFC Striatum (caudate nucleus, putamen) Nucleus accumbens Prelimbic regions Amygdala ACC Posterior parietal cortex Hippo-campus VTA Substantia nigra
Function related to ADHD Inhibition, executive functions (dlPFC) Motor control, motivation
transmits (afference) / receives (efference) DA transmits and receives DA receives DA receives DA receives DA transmits to striatum (caudate nucleus and putamen)
DAT (fmol/mg)37 rare frequent (154) frequent (54.8; authors speak of fmol/g; this seems to be an oversight) (12.3) frequent (dentate gyrus) (5.3) present in VTA lateral, hardly ever in VTA medial 38 frequent; DAT also causes DA release, postsynaptically, when DA levels are very low3937
NET (fmol/mg)37 medium, can reabsorb DA (16.2) very low (3.4) high proportion of DA degradation (19.5) high proportion of DA degradation (16)
extracellular DA low low
DA vesicles little much
COMT high low
D1 receptor (activating) frequent frequent
D5 receptor (activating) rare rare
D2 receptor (inhibitory) rare frequent
D3 receptor (inhibitory) rare frequent
D4 receptor (inhibitory) frequent; here more sensitive to NE than to DA.40 rare

DA = dopamine; NE = noradrenaline


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