Depression is primarily thought to be caused by a disorder of the noradrenaline and serotonin metabolism in the brain.
In addition, studies indicate that disorders of the dopamine system (as also exist in ADHD) can also cause symptoms of depression. There are many indications that the reward system (especially the mesolimbic dopaminergic system) is involved in anhedonia, dysthymia and amotivation in depression.
Hyperactivity in the subgenual cingulate gyrus (Brodman area 25 of the PFC), which correlates with depression, is reduced by effective depression treatment
Brodman area 25 is extremely rich in serotonin transporters and acts as a hub for an extensive network that regulates sadness. This includes
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Hypothalamus and brain stem
- influence changes in appetite and sleep
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Amygdala and insula
- influence mood and anxiety
- In depression, the amygdala reacts hyperactively to (especially negative) emotionally charged stimuli.
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Hippocampus
- important role in memory formation
- some parts of the frontal cortex
- which are responsible for self-esteem
Acute activation of the dopamine system by amphetamine or stressors is followed by depression of dopaminergic neuron firing. If there are chronic stressors that end, the depression-like state persists over a longer period of time.
Animal models of depression use chronically uncontrollable or unpredictable stressors that trigger helplessness. The duration of the stressors correlates with the extent and duration of the subsequent depressive state and, in parallel, with a prolonged decrease in the activity of dopamine neurons in the medial VTA (by about 50 %). The medial VTA projects in particular into the (reward-relevant) ventromedial nucleus accumbens. This decrease in phasic dopamine firing could be completely reversed by inactivating the infralimbic PFC or the basolateral amygdala, whose hyperactivity inhibits the phasic activity of dopaminergic neurons. Activation of the infralimbic prefrontal cortex (ilPFC) can greatly reduce the tonic activity of dopamine neurons via the basolateral amygdala.
Inactivation of ilPFC increases phasic dopamine neuron activity via the ventral subiculum of the hippocampus.
It is possible that the reduced phasic dopaminergic activity of DA neurons caused by chronic mild stressors in the depression animal model is caused by hyperactivity in the ilPFC, leading to an overdrive of the amygdala and, via the ventral pallidum, a decrease in the number of dopaminergic neurons firing in the medial (reward-related) VTA.
Not all individuals are equally susceptible to depression. One study selected mice according to their susceptibility to depression following social defeat. Depression-prone mice showed hyperactivity of the dopamine neurons ex vivo as in vivo. This susceptibility to depression can be reproduced by bursts in DA neurons.
When DA neuron hyperactivity is normalized, depression symptoms subside, just as DA neuron hyperactivity normalizes when antidepressants effectively reduce depression symptoms.
Depression resilience may depend on the homeostatic plasticity of intrinsic conductance in VTA neurons projecting to the NAc. Complete suppression of DA neuron activity during forced swimming and sucrose preference test induced a depression-like phenotype.
Normally, the ventral subiculum of the hippocampus (hippocampus-vSub) activates the nucleus accumbens, which inhibits the ventral pallidum, increasing the tonic dopaminergic activity of the VTA and increasing the response to afferent drive.
Activation of the ilPFC indirectly inhibits the hippocampal vSub and simultaneously activates the basolateral amygdala, which in turn activates the ventral pallidum, resulting in reduced activity of the tonic dopamine neuron population. Activation of the ilPFC thus inhibits the response of the dopamine system to phasic events via activation of the basolateral amygdala.
In contrast, inhibition of the ilPFC removes tonic inhibition of the hippocampal vSub, which increases projections to the nucleus accumbens and thereby inhibits the ventral pallidum, increasing tonic dopaminergic activity. Inhibition of the ilPFC therefore increases the responsiveness of the dopamine system via the disinhibition of the hippocampal vSub.
Promotion of phasic dopamine activity by very low extracellular dopamine levels is unlikely to result from “normally low” tonic dopamine firing. Only an abnormally low tonic extracellular dopamine level (as suspected in ADHD) leads to an upregulation of the autoreceptors, so that phasic dopamine triggered by stimuli is increased.
Drugs that reduce dopamine turnover in the brain, such as neuroleptics or reserpine, can trigger depressive episodes.
Conversely, the dopamine agonist bromocriptine has shown antidepressant properties in some studies.
Similarly, a study of (albeit only 5) depressive patients showed a positive effect of augmenting (in addition to SSRI) administration of methylphenidate, which is known to increase dopamine and noradrenaline levels through reuptake inhibition and DAT efflux.
The fact that anhedonia is more similar to dysphoria than to the symptoms of moderate or severe depression could be understood as an indication that the dysphoria typical of ADHD (during inactivity) is originally caused by the dopamine deficiency typical of ADHD (primarily in the striatum). This would also explain why stimulant treatment (especially amphetamine medication) can have a positive influence on dysphoria. In addition, anhedonia also occurs as an original ADHD symptom.
Chronic stress correlates with dopamine depletion in the brain and can be treated with dopaminergic substances. More on this at ⇒ Changes in the dopaminergic system due to chronic stress In the article ⇒ ADHD as a chronic stress regulation disorder in the chapter ⇒ Stress.
