Neurophysiological mechanisms of action on behavior by immune responses.

The stress hormones of the HPA axis (CRH, vasopressin, ACTH) mediate not only immune responses but also behavioral responses. These behavioral triggers of stress hormones explain some of the ADHD symptoms, but probably not all.

Pro-inflammatory and anti-inflammatory cytokines of the immune system activated by the various stress hormones also exhibit behavioral aspects.

A metastudy of 67 studies of about 4000 children and adolescents shows that inflammatory markers are elevated in quite a few neuropsychiatric disorders:¹

• Autism Spectrum Disorders (ASD)
• Major depressive disorder (MDD)
• Bipolar disorder (BD)
• Post-traumatic stress disorder (PTSD)
• Obsessive Compulsive Disorder (OCD)
• Tourette’s Disorder (TD)
• Attention deficit hyperactivity disorder (ADHD) and
• Schizophrenia (SZ)

Further, correlations were found between atopic immune system conditions and ADHD.²

One hypothesis postulates that an increased reactivity of the immune system leads to a greater withdrawal behavior.³ This could be justified evolutionary-biologically by the fact that a higher reactivity of the immune system costs more resources. Since any activation of the immune defense requires effort, it would be conclusive if individuals with a lighter/faster activated immune defense are more likely to keep their distance from infection sites (other individuals) than those with a lower risk of (effort-intensive) immune system activation. It could be concluded that social phobia correlates with an easily activated immune system.

However, individuals with high extraversion were actually found to have a more highly activated immune system than individuals with high agreeableness. Another study found increased pro-inflammatory gene expression for extraversion, while it was decreased for conscientiousness.⁴

Immune system activation due to infections leads to social withdrawal.⁵ In people with high social withdrawal, one (very small, n = 14) study found increased immune activation of pro-inflammatory cytokines with concomitant decreased B lymphocyte function and IFN-α response in terms of gene expressions. Anti-inflammatory glucocorticoid response elements (GRE) were decreased and response elements for pro-inflammatory NF-κBRel transcription factors were increased.⁶

• 1. Neurophysiological mechanisms mediating behavioral effects of inflammatory responses
• 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 action 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 action on the serotonin system

1. Neurophysiological mechanisms mediating behavioral effects of inflammatory responses¶

Basic neurophysiological mechanisms of mediation of behavioral effects by inflammatory responses are discussed:⁷

• Glia activation⁸
• Neuronal damage and neurodegeneration⁹
• Increased oxidative stress¹⁰
• Reduced BDNF levels¹¹
• Blood-brain barrier disorders¹²
• Altered neurotransmitter metabolism¹³

2. Behavioral changes due to cytokine effects on neurotransmitters¶

Inflammation affects several brain neurotransmitter systems, including serotonin, dopamine, norepinephrine, and glutamate pathways, as well as the kynurenine pathway, which produces the neurotoxic metabolite quinolinic acid. Disruption of neurotransmitter systems correlates with inflammation-related changes that mediate motivation and motor function as well as fear, arousal, and alarm.¹⁴¹⁵

The innate immune system as well as pro-inflammatory cytokines directly affect dopamine in the basal ganglia, thereby influencing motivation (reduction) and motor function (slowing).¹⁶¹⁷ Inflammatory responses cause a preference for avoiding losses over achieving gains.¹⁸ Endotoxin decreases striatal activity to offered rewards.¹⁹

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

Dopamine has the unusual property of increasing upregulation by 500% of

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

trigger.²²

• IFN-γ and
• IL-4

were not altered by dopamine via T cells.²²

Inflammation and disease stress working memory by reducing the ability of short-term memory to process environmental stimuli. This effect is likely responsible for the changes in cognition caused by inflammation.⁵ In ADHD, working memory is significantly impaired.

3. Inflammatory processes and dopamine¶

Much of the presentation of the linkage between the inflammatory elements of the immune system and dopamine is based on the work of Felger.²³

Inflammatory processes have a direct influence on the dopaminergic system.

3.1. Pro-inflammatory cytokines cause¶

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

3.1.1. Behavioral symptoms due to pro-inflammatory cytokines¶

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

• Anhedonia²³²⁴
• Fatigue²³
• Psychomotor slowdown²³²⁴

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, norepinephrine and dopamine.

Dopamine is synthesized from phenylanaline (by means of the enzyme phenylanaline hydroxlase) to tyrosine, which is synthesized (by means of the enzyme tyrosine hydroxlase) to L-dopa and from that 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 norepinephrine.
Thus, a deficiency of BH4 impairs the synthesis of dopamine (and norepinephrine).
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 inducible NOS (iNOS) activity, which binds BH4 (serving as a cofactor for nitric oxide synthases (NOS)). This causes 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 decrease BH4 availability, which limits dopamine synthesis.²⁸

Peripherally injected IFN-α decreases BH4 levels in amygdala and raphe nuclei in 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) reduced BF4 levels in neurons by 90%, as did ciliary neurotrophic factor (CNTF), whereas IL-6 or TNF-alpha did not significantly alter BF4.³¹

In ADHD, dopamine synthesis (e.g., using BH4) does not appear to be impaired, as administration of L-dopa shows no effect on ADHD symptomatology.

3.1.2.2. Increase in tyrosine hydroxylase¶

An increase in tyrosine hydroxylase by 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 action of VMAT2 promotes oxidative stress¶

The vesicular monoamine transporter (VMAT, VMAT2) is involved in the incorporation of dopamine into vesicles. Sex differences exist in neuronal VMAT2 activity that explain the differential response to methamphetamine. Packaging of dopamine in dopaminergic neurons by VMAT2 is required to prevent damage from oxidized dopamine during oxidative stress or after metamphetamine feeding. Mice with as little as 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 move dopamine from the vesicles of the sending synapse (presynapse) into the synaptic cleft. At the same time, they have the task of reabsorbing dopamine that has been taken up by the receiving synapse (postsynapse) and subsequently returned to the synaptic cleft so that it can be stored in the vesicles for reuse. If the DAT are too active or too many (which is often the case in ADHD), the DAT will already reabsorb the dopamine freshly added to the synaptic cleft by the sending synapse before it could transmit the signal at the postsynapse. This leads to signal transmission disturbances.

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

Protein kinase C (PKC) decreases dopamine reuptake and DAT number.³⁴ Mitogen-activated protein kinase (MAPK) pathways appear to activate the dopamine transporter (DAT) in contrast. Striatal cells with particularly active MAPK showed increased dopamine reuptake, whereas with 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¶

Affected individuals with neuropsychiatric disorders due to HIV infection are thought to have increased expression of DAT as a consequence of resultant neuroinflammation,³⁵ whereas in HIV without encephalitis, unchanged DAT expression was found with decreased DAT activity. In addition, decreased levels of tyrosine hydroxylase and phosphorylated tyrosine hydroxylase were detected. Furthermore, the D2 receptor was decreased and the D3 receptor was increased in expression.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 slightly lesser extent, IFN-α) activate indoleamine 2,3-dioxygenase (IDO) in peripheral immune cells or microglia. IDO converts tryptophan to kynurenine, this (by kynurenine aminotransferase) to kynurenic acid and quinolinic acid.¹⁵ Kynurenic acid acts as a glutamate receptor antagonist, which decreases glutamate neurotransmission. This in turn inhibits the release of dopamine in the striatum.
Excessive release of glutamate and quinolinic acid due to inflammation may increase oxidative stress and excitotoxicity.

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

For a more detailed account, see ⇒ How IFN-α neurophysiologically triggers depression In the section ⇒ Depression and dysphoria in ADHD in the section ⇒ Diagnostics

4. Inflammatory processes and serotonin¶

4.1. Cytokine action on the serotonin system¶

IFN-γ, as well as, to a slightly lesser extent, IFN-α, decrease tryptophan, which is necessary for the synthesis of serotonin. Therefore, IFN may decrease serotonin levels.¹⁵

Stimulation of p38 mitogen-activated protein kinase (MAPK) can increase serotonin transporter expression and function, and thus serotonin reuptake, which can induce serotonin deficiency.³⁸³⁹ MAPK and its mediated serotonin transporter activation are 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 serotonin synthesis. BH4 is therefore essential for the synthesis of serotonin, norepinephrine 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, might be recommended to counteract the impairment of tryptophan generation. We know of cases of treatment-resistant depression in which 5-HTP produced immediate improvement, at least temporarily. Since 5-HTP is converted exclusively to serotonin, 5-HTP is helpful only with respect to mood problems, but not with respect to the primarily dopaminergic and noradrenergic ADHD symptoms.
One study suggests that tryptophan levels are reduced in adult ADHD sufferers 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 tended to find increased tryptophan levels in children with ADHD.⁴¹
Vitamin B12 supports the generation of tetrahydrobiopterin (BH4).

Endotoxin activates serotonin transporters (which can induce a serotonin deficit) and decreases 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