3. Interactions of the dopaminergic brain areas.

• 3. Interactions of dopaminergic brain areas
  • 3.1. Nucleus accumbens as a control center between emotion and action
  • 3.2. The dopamine seesaw between PFC and subcortical regions (including striatum)
  • 3.3. The dopaminergic interaction of nucleus accumbens, hippocampus, and mPFC
    • 3.3.1. Activity ratio of hippocampus to mPFC regulates activity of nucleus accumbens
      • 3.3.1.1. Hippocampus more active than mPFC: nucleus accumbens active
      • 3.3.2.2. MPFC more active than hippocampus: nucleus accumbens inhibited
  • 3.4. Interaction locus coeruleus and midbrain
  • 3.5. Dopamine and functional connectivity
  • 3.6. Dopamine elements in different brain areas

3. Interactions of dopaminergic brain areas¶

3.1. Nucleus accumbens as a control center between emotion and action¶

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

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

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

3.2. The dopamine seesaw between PFC and subcortical regions (including striatum)¶

High dopamine levels in the PFC cause decreased 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 tonic dopamine release in the nucleus accumbens via presynaptic contacts on dopaminergic nerve endings.
The basolateral amygdala is dopaminergically informed by the PFC of its stress responses, and the amygdala is also dopaminergically addressed by the ventral tegmentum in a stress-dependent manner.⁴
The mPFC projects directly and indirectly via the pedunculopotent tegmental nucleus to 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-at any age-increase subcortical dopaminergic activity, especially in the nucleus accumbens in the striatum, causing behavioral deficits in addition to biochemical changes.⁶⁷⁸⁹
It probably depends on which side of the brain the lesion occurs. The dopaminergic activity of subcortical regions apparently depends on the level of dopamine in the mPFC in the two cerebral hemispheres. Uncontrollable stress increased dopamine especially in the right cortex. Dopamine deficiency in the left or right PFC, mPFC, or anterior cingulate increased stress vulnerability. One study found increased stress-induced gastric ulcer formation from chronic cold stress in rats.¹⁰

• Dopamine Deficiency

  • In the right cortex caused¹⁰
    • Dopamine levels in the striatum decreased bilaterally (in rats)
  • In the left cortex caused¹⁰
    • Dopamine turnover increased bilaterally in the amygdala (in rats)
  • Induced bilaterally in the cortex (in rats)¹⁰
    • Dopamine level in the right nucleus accumbens decreased
    • Dopamine turnover increased in the left nucleus accumbens
    • Dopamine turnover decreased in the right amygdala
    • Dopamine levels increased in the left amygdala
  • In the mPFC caused
    • Dopamine release in the nucleus accumbens increased¹¹
  • In the PFC caused
    • Even mild stress increases dopamine release in the nucleus accumbens; cortisol levels increased as a result¹²(bei neugeborenen Ratten)
  • In the PFC caused
    • Increased amphetamine sensitivity due to increased dopamine sensitivity, probably resulting from increased density of dopamine D2 receptors in the nucleus accumbens.¹³(bei Ratten)

• Dopamine release

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

Rats born with oxygen deprivation during cesarean section showed increased dopaminergic response in the nucleus accumbens, hyperactivity, and increased dopamine transporter density in the right PFC. D1 and D2 receptors were unchanged. Chronic stress also showed dopamine deficiency in the right PFC.¹⁵

Carriers of the COMT Val/Val polymorphism, which synthesizes more COMT in the PFC, resulting in faster dopamine depletion, thus lower dopamine levels in the PFC, showed lower tonic and increased phasic dopamine levels in subcortical brain regions.¹⁶

There seems to be a kind of “dopamine seesaw” between the PFC and the striatum - at least in healthy individuals. Little dopamine in the PFC is supposed to correlate with much 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, since a 15-year more recent study found that an amphetamine-induced dopamine increase 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 correspond to those induced by environmental influences.²⁸

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

For a more in-depth account of the following presentation, see Klein.²⁹

The nucleus accumbens is addressed by the mPFC and the hippocampus. Whether there is a long-term enhancement of nucleus accumbens responses to stimuli from the PFC or the hippocampus (neurological correlate: long-term potentiation, learning effects) depends on dopamine levels elsewhere.
Stimuli from the hippocampus enhanced learning in the nucleus accumbens when D1 agonists (stimulating) were given, whereas D1 antagonists (inhibitory) blocked long-term potentiation.³⁰³¹
Stimuli from the mPFC enhanced learning in the nucleus accumbens when D2 antagonists (inhibitory) were given, whereas D1 agonists (excitatory) blocked long-term potentiation.³⁰³¹
This leads to the following hypothesis by Goto and Grace:

3.3.1. Activity ratio of hippocampus to mPFC regulates activity of 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 sends to the mPFC.
The consequences are:

• Nucleus accumbens has increased activity
  • Because hippocampus and mPFC are active simultaneously
  • 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 in the presence of NMDA receptor activity
      • Thereby long-term potentiation of hippocampal inputs.
    • Simultaneous D2 receptor-dependent long-term depression of prefrontal inputs
      • Probably through various 2nd messenger systems³¹
        • 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
    • Thereby reduced tonic dopamine release in the nucleus accumbens
  • Presynaptic D2 receptor activity is reduced
  • Signals from the mPFC to the nucleus accumbens are amplified
  • Thereby long-term potentiation of the mPFC inputs³¹

Long-term potentiation of inputs to the nucleus accumbens from the hippocampus as well as from the PFC can be reversed by electrical stimulation of nerve fibers with high repetition frequency (causing activation) of the other region.³¹

3.4. Interaction locus coeruleus and midbrain¶

In anesthetized rats, stimulation of the locus coeruleus with a single pulse produced excitation followed by inhibition of the electrical activity of single dopamine neurons in the midbrain (VTA, substantia nigra). Burst stimulation produced a longer-lasting inhibition. Reserpine suppressed this response, suggesting a noradrenergic-mediated response.³²

3.5. Dopamine and functional connectivity¶

Dopamine appears to specifically affect the functional connectivity of certain brain regions. Amisulpride (a D2/D3 antagonist) increased functional connectivity from the putamen to the precuneus and from the ventral striatum to the precentral gyrus, according to one study. 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.³³

3.6. Dopamine elements in different brain areas¶

DA = dopamine; NE = norepinephrine