Neurophysiological mechanisms of action on behavior through immune reactions

The stress hormones of the HPA axis (CRH, vasopressin, ACTH) not only mediate immune responses, but also behavioral responses. These behavioral triggers of the stress hormones explain some of the ADHD symptoms, but probably not all of them.
Proinflammatory and anti-inflammatory cytokines of the immune system, which are activated by the various stress hormones, also have behavioral aspects. The mediation of behavioral effects by inflammatory responses is based on various neurophysiological mechanisms. These include glial cell activation, neuronal damage, increased oxidative stress, decreased BDNF levels, blood-brain barrier disruption and altered neurotransmitter metabolism such as serotonin, dopamine, noradrenaline and glutamate. The effects on these systems lead to changes in motivation, motor function, anxiety, arousal and alertness.
Inflammation has a direct influence on the dopaminergic system and reduces dopamine levels in the brain. Dopamine in turn influences the release of inflammation-related cytokines. Inflammatory processes can cause oxidative stress and neurotoxic effects via the glutamate balance. A deficiency of tetrahydrobiopterin (BH4), an enzyme cofactor required for the synthesis of serotonin and dopamine, can lead to an impairment of serotonin synthesis.

Inflammatory markers are elevated in a number of neuropsychiatric disorders:¹

• ADHD
• ASS
• Depression
• Bipolar disorder
• Post-traumatic stress disorder (PTSD)
• Obsessive-compulsive disorder
• Tourette’s disorder
• Schizophrenia

Correlations were also found between atopic immune system conditions and ADHD.²

An increased reaction intensity of the immune system could lead to greater withdrawal behavior.³ Immune system activation due to infections leads to social withdrawal.⁴ In people with high social withdrawal behavior, a (very small) study found increased immune activation of proinflammatory cytokines with decreased B-lymphocyte function and IFN-α response. Anti-inflammatory glucocorticoid response elements were decreased and response elements for proinflammatory NF-κBRel transcription factors were increased.⁵ This could be explained evolutionarily by the fact that a higher reactivity of the immune system costs more resources. Since every activation of the immune defense requires effort, it would be logical if individuals with a more easily/quickly activated immune defense tend to keep their distance from infection foci (other individuals) than those with a lower risk of (costly) immune system activation. From this it could be concluded that social phobia correlates with an easily activated immune system.
However, individuals with high extraversion have a more activated immune system than individuals with high agreeableness. Another study found increased pro-inflammatory gene expression for extraversion, while it was reduced for conscientiousness.⁶

• 1. Neurophysiological mechanisms of the mediation of behavioral effects by inflammatory reactions
• 2. Behavioral changes due to cytokine effects on neurotransmitters
• 3. Inflammatory processes and dopamine
  • 3.1. Pro-inflammatory cytokines cause
    • 3.1.1. Behavioral symptoms due to pro-inflammatory cytokines
    • 3.1.2. Cytokine effects on the dopamine system
      • 3.1.2.1. Reduction of tetrahydrobiopterin (BH4) inhibits dopamine synthesis
      • 3.1.2.2. Increase in tyrosine hydroxylase
      • 3.1.2.3. Reduced expression or effect of VMAT2 promotes oxidative stress
      • 3.1.2.4. Increased expression or effect of DAT
        • 3.1.2.4.1. Increased expression or effect of DAT by VMAT and MAPK
        • 3.1.2.4.2. Increased DAT in HIV encephalitis
    • 3.1.3. Reduced transmission of glutamate
• 4. Inflammatory processes and serotonin
  • 4.1. Cytokine effect on the serotonin system

1. Neurophysiological mechanisms of the mediation of behavioral effects by inflammatory reactions¶

The basic neurophysiological mechanisms of the mediation of behavioral effects by inflammatory reactions are discussed:⁷

• Glial activation⁸
• Neuronal damage and neurodegeneration⁹
• Increased oxidative stress¹⁰
• Reduced BDNF levels¹¹
• Disorders of the blood-brain barrier¹²
• Altered neurotransmitter metabolism¹³

2. Behavioral changes due to cytokine effects on neurotransmitters¶

Inflammation affects various neurotransmitter systems of the brain, including serotonin, dopamine, norepinephrine and glutamate pathways, as well as the kynurenine pathway, which produces the neurotoxic metabolite quinolinic acid. Disruptions in neurotransmitter systems correlate with inflammation-induced changes that mediate motivation and motor function as well as anxiety, arousal and alarm.¹⁴¹⁵

The innate immune system and pro-inflammatory cytokines have a direct influence on dopamine in the basal ganglia, thereby influencing motivation (reduction) and motor skills (slowing down).¹⁶¹⁷ Inflammatory reactions cause a preference for avoiding losses over achieving gains.¹⁸ Endotoxin reduces the activity of the striatum in response to offered rewards.¹⁹

Dopamine transporters, which are prominently involved in the pathogenesis of ADHD, are abundant on human T cells.²⁰
In STAT6-deficient mice, DAT in the striatum is reduced, inducing hyperactivity (where STAT6 interacts closely with cytokines and growth factors).²¹

Dopamine has the unusual property of triggering the upregulation of cytokines by 500%:²²

• TNFα within 24 hours, via the D3 receptor
• IL-10 within 72 hours, via the D2 receptor
• TNFα within 24 hours and IL-10 within 72 hours via the D1 / D5 receptors
• IFN-γ remained unchanged
• IL-4 remained unchanged

Inflammation and disease put a strain on working memory by reducing the ability of short-term memory to process environmental stimuli. This effect is probably responsible for the changes in cognition caused by inflammation.⁴ In ADHD, working memory is significantly impaired.

3. Inflammatory processes and dopamine¶

Much of the description of the link between the inflammatory elements of the immune system and dopamine is based on Felger’s work.²³

Inflammatory processes have a direct influence on the dopaminergic system.

3.1. Pro-inflammatory cytokines cause¶

• Reduced reactions of the ventral striatum to hedonic reward stimuli (anhedonia)²³²⁴
• Reduced dopamine levels in the striatum²³
• Reduced levels of dopamine and dopamine metabolites in the cerebrospinal fluid²³
• Reduced functional connectivity of striatal reward systems due to CRP, IL-6, IL-1beta and IL-1 RA.²³²⁵¹⁷ Reduced connectivity between brain areas is thought to be a (co-)cause of ADHD and is improved by stimulants. More on this at ⇒ ** Effect on connectivity between brain regions in the article*⇒ Methylphenidate (MPH) for ADHD*.

3.1.1. Behavioral symptoms due to pro-inflammatory cytokines¶

The effects of pro-inflammatory cytokines correlate with (depressive) behavioral symptoms

• Anhedonia²³²⁴
• Tiredness²³
• Psychomotor deceleration²³²⁴

3.1.2. Cytokine effects on the dopamine system¶

Cytokines act on the dopamine system through various mechanisms.

3.1.2.1. Reduction of tetrahydrobiopterin (BH4) inhibits dopamine synthesis¶

BH4 is therefore essential for the synthesis of serotonin, noradrenaline and dopamine.

Dopamine is synthesized from phenylanaline (via the enzyme phenylanaline hydroxlase) to tyrosine, which is synthesized (via the enzyme tyrosine hydroxlase) to L-dopa and from there to dopamine.
Tetrahydrobiopterin (BH4) is involved (as an enzyme cofactor of tyrosine hydroxlase) in the synthesis of tyrosine from phenylanaline and (as an enzyme cofactor of phenylanaline hydroxlase) in the synthesis of L-dopa from tyrosine. Dopamine is in turn a precursor of noradenalin.
A lack of BH4 thus impairs the synthesis of dopamine (and noradrenaline).
Vitamin B12 supports the generation of tetrahydrobiopterin (BH4).

Inflammation and cytokines, e.g. IFN-alpha, can reduce the availability of BH4.²⁶²⁷ This impairs the synthesis of dopamine and serotonin.

Inflammation increases the activity of inducible NOS (iNOS), which binds BH4 (which acts as a cofactor for nitric oxide synthases (NOS)). This causes the formation of ROS (oxygen radicals) instead of NO.²⁸ BH4 thus regulates the formation of superoxides.²⁹ ROS cause oxidative stress, which in turn contributes to the oxidative reduction of BH4 itself. BH4 oxidizes very easily.²⁸
These mechanisms reduce BH4 availability, which limits dopamine synthesis.²⁸

Peripherally injected IFN-α lowers BH4 levels in the amygdala and raphe nuclei of rats by increasing NO synthesis. When NO synthesis is inhibited, IFN-α loses its inhibitory effect on BH4 and dopamine levels in the brain.³⁰

Cardiotrophin-1 (CT-1) as well as ciliary neurotrophic factor (CNTF) reduced BF4 levels in nerve cells by 90 %, while IL-6 or TNF-alpha did not cause any significant change in BF4.³¹

In ADHD, dopamine synthesis (e.g. via BH4) does not appear to be impaired, as the administration of L-dopa has no effect on ADHD symptoms.

3.1.2.2. Increase in tyrosine hydroxylase¶

An increase in tyrosine hydroxylase due to IL-1-beta indicates increased dopamine turnover in the hypothalamus. The change correlated with increased ACTH levels with unchanged prolactin levels.³²

3.1.2.3. Reduced expression or effect of VMAT2 promotes oxidative stress¶

The vesicular monoamine transporter (VMAT, VMAT2) is involved in the storage of dopamine in the vesicles. There are sex differences in neuronal VMAT2 activity that explain the different response to methamphetamine. Packaging of dopamine in dopaminergic neurons by VMAT2 is required to prevent damage from oxidized dopamine during oxidative stress or after methamphetamine intake. Mice with only 5 to 10 % VMAT2 showed rapid damage to such neurons.³³

3.1.2.4. Increased expression or effect of DAT¶

3.1.2.4.1. Increased expression or effect of DAT by VMAT and MAPK¶

Dopamine transporters have the task of reabsorbing dopamine that has been taken up by the receiving synapse (postsynapse) and then released back into the synaptic cleft so that it can be stored in the vesicles for reuse. DAT can also work in reverse, releasing dopamine from the cytoplasm into the extracellular space (DAT efflux).
If the DAT are too active or too many (which is often the case with ADHD), the DAT absorb the dopamine freshly released into the synaptic cleft by the transmitting synapse before it has been able to transmit the signal at the postsynapse. This leads to signal transmission disorders.

Dysregulation of DAT and VMAT can increase dopamine in the cell fluid, which can trigger auto-oxidation, the formation of ROS (reactive oxygen species = oxygen radicals) and the formation of neurotoxic quinones. Higher ROS levels can lead to oxidative stress.

Protein kinase C (PKC) reduces dopamine reuptake and DAT numbers.³⁴ Mitogen-activated protein kinase (MAPK) pathways appear to activate the dopamine transporter (DAT). Striatal cells with particularly active MAPK showed increased dopamine reuptake, whereas in inhibited MAPK they correlated with decreased DA reuptake in a dose- and time-dependent manner.³⁴

3.1.2.4.2. Increased DAT in HIV encephalitis¶

In those affected by neuropsychiatric disorders due to HIV infection, increased expression of DAT is assumed as a result of the resulting neuroinflammation,³⁵ while unchanged DAT expression with reduced DAT activity was found in HIV without encephalitis. In addition, reduced levels of tyrosine hydroxylase and phosphorylated tyrosine hydroxylase were found. Furthermore, the D2 receptor was reduced and the D3 receptor was increased.³⁶

IFN-α, given chronically, showed no change in DAT binding in monkeys.³⁷

3.1.3. Reduced transmission of glutamate¶

IFN-γ (and, to a lesser extent, IFN-α) activate indoleamine 2,3-dioxygenase (IDO) in peripheral immune cells or microglia. IDO converts tryptophan to kynurenine, which is converted (by kynurenine aminotransferase) to kynurenic acid and quinolinic acid.¹⁵ Kynurenic acid acts as a glutamate receptor antagonist, which reduces glutamate neurotransmission. This in turn inhibits the release of dopamine in the striatum.
Excessive release of glutamate and quinolinic acid due to inflammation can increase oxidative stress and excitotoxicity.

This pathway is successfully treated with glutamate receptor antagonists such as ketamine.

A more detailed description can be found at ⇒ How IFN-α triggers depression neurophysiologically In the section ⇒ Depression and dysphoria in ADHD in the chapter ⇒ Diagnostics

4. Inflammatory processes and serotonin¶

4.1. Cytokine effect on the serotonin system¶

IFN-γ and, to a lesser extent, IFN-α, reduce tryptophan, which is required for the synthesis of serotonin. IFN can therefore reduce serotonin levels.¹⁵

Stimulation of p38 mitogen-activated protein kinase (MAPK) can increase the expression and function of the serotonin transporter and thus serotonin reuptake, which can trigger serotonin deficiency.³⁸³⁹ MAPK and the serotonin transporter activation it mediates is activated by IL-1-β and TNF-α in a dose- and time-dependent manner and inhibited by IL-1-RA.³⁸

BH4 is also required for the activities of tryptophan hydroxylase, which is a rate-limiting enzyme in the synthesis of serotonin. BH4 is therefore essential for the synthesis of serotonin, noradrenaline and dopamine (see above).
BH4 deficiency is a relevant pathway for understanding depression. If elevated IFN-alpha is detected, treatment with 5-HT, a prodrug of serotonin, could be recommended to counteract the impairment of tryptophan generation. We know of cases of treatment-resistant depression in which 5-HTP brought about an immediate improvement, at least temporarily. As 5-HTP is only converted to serotonin, 5-HTP is only helpful with regard to mood problems, but not with regard to ADHD symptoms, which are primarily caused by dopaminergic and noradrenergic factors.
One study suggests that tryptophan levels are reduced in adults with ADHD and that the degree of reduction in the level of tryptophan and its metabolites (= breakdown products) correlates with the severity of ADHD symptoms.⁴⁰ Another study found that tryptophan levels tended to be higher in children with ADHD.⁴¹
Vitamin B12 supports the generation of tetrahydrobiopterin (BH4).

Endotoxin activates serotonin transporters (which can trigger a serotonin deficit) and reduces physical activity in mice in stress tests. The endotoxin-induced reduction in physical activity does not occur in mice with deactivated serotonin transporters and in mice whose IL-1 receptors were inhibited by an antagonist.⁴²